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Deep learning method helps to improve research into spinal ganglia
2025
University Hospital Würzburg, Wuerzburg, Germany
Dorsal root ganglia (DRG) are involved in processing sensation and pain, but their exact function is not fully understood. New magnetic resonance imaging (MRI) techniques allow for the study of DRG within the body. Certain DRG measurements in MRI, such as volume and T2w signal, have been identified as potential indicators (biomarkers) that may be related to biochemical and genetic factors as well as neuropathic pain. To better utilize these biomarkers, automated methods for evaluating DRG images are needed, as DRG are currently mostly marked manually on the images. In this study, such an automated method based on deep learning was developed. A computer network (CNN) was trained with the nnU-Net software to identify DRG on detailed 3D MRI images (220 DRGs). The automated markings of the DRG were similarly accurate to the manual ones (accuracy of 0.89 vs. 0.87) and 10 times faster. The method was tested on patients with Fabry disease, a disease in which the DRG change. The computer network was able to detect the known changes of the DRG in this disease. Thus, an automated method for marking the DRG in MRI images was developed, and it was shown that it can be used to study DRG changes, e.g., in Fabry disease.
Automated segmentation of the dorsal root ganglia in MRI
Magnus Schindehütte
Added on: 05-02-2025
Human assembloid model of the ascending neural sensory pathway
2025
Stanford University, Stanford, USA
Understanding the mechanisms underlying the development of the human sensory system is crucial for comprehending and treating sensory-related disorders. In the present study, a novel in vitro model of the ascending somatosensory pathway was developed. This model is based on a four-part assembloid generated from human pluripotent stem cells. The assembloid integrates somatosensory, spinal, thalamic, and cortical organoids to model the spinothalamic tract. Transcriptome analysis confirmed the presence of key cell types of this neuronal network. Rabies tracing and calcium imaging demonstrated that sensory neurons connect to dorsal spinal cord neurons, which in turn connect to thalamic neurons. Following noxious chemical stimulation, calcium imaging of the assembloid revealed a coordinated response. Furthermore, extracellular recordings and imaging indicated synchronized activity within the assembloid. Loss of a sodium channel, associated with pain insensitivity, disrupted synchrony throughout the assembloid, whereas a gain-of-function variant of the SCN9A gene, linked to extreme pain conditions, induced hypersynchrony. The establishment of this model could contribute to an improved understanding of sensory circuits and facilitate the development of therapies.
Human assembloid model of the ascending neural sensory pathway
Sergiu P. Paşca
Added on: 05-02-2025
Integration of microglia in retinal organoids
2025
Institute of Science and Technology Austria (ISTA), Klosterneuburg, Austria
Infections during pregnancy can endanger the development of the baby's brain and eyes. However, knowledge about the safe use of anti-inflammatory drugs during pregnancy is still limited.
Although the functional effects of viral stimulation have been studied in brain organoid models derived from human induced pluripotent stem cells (hIPSC), these models generally lack microglia, which are susceptible to and promote inflammation. In addition, microglia are actively involved in neuronal development.
To investigate this in more detail, hIPSC-derived microglial cells were generated here and integrated into retinal organoids. In this model, a viral infection was mimicked and it was observed how the microglia react and interact with other cells in the retina. It was shown that the microglia release inflammatory substances during this simulated infection and stimulate cell growth in the retina.
At the same time, the effect of the anti-inflammatory drug ibuprofen was investigated. It was able to attenuate some of the changes triggered by the simulated infection. Of particular note was that ibuprofen was able to normalize the activity of certain nerve cells in the retina - but this only occurred when microglia were present.
These findings highlight the importance of microglia in responding to infection during development and provide insights into the mechanisms by which ibuprofen may exert protective effects. It appears that ibuprofen exerts its effect by influencing certain enzymes that are active in both microglia and other cells of the retina.
Microglia determine an immune-challenged environment and facilitate ibuprofen action in human retinal organoids
Sandra Siegert
Added on: 04-29-2025
Patient study to investigate the visual processing of distracting stimuli
2025
Vrije Universiteit Amsterdam, Amsterdam, Netherlands
Through experience, humans can learn to suppress locations that frequently contain distracting stimuli. However, the neural mechanism underlying learned suppression remains largely unknown. In the present study, two types of brain activity measurements (steady-state visually evoked potentials (SSVEPs)and event-related potentials (ERPs)) were combined to investigate the mechanism behind statistically learned spatial suppression. Brain activity was recorded using a 64-electrode cap placed on the participants' scalp. Additionally, eye movements were recorded using electrodes and an eye-tracking system. Twenty-four male and female participants performed a version of the additional singleton search task in which one location frequently contained a distractor stimulus. The search stimuli constantly flickered on and off the screen, resulting in steady state entrainment. Prior to search onset, no differences in the SSVEP response were found, although a post-hoc analysis did reveal proactive alpha lateralization. Following search onset, clear evoked differences emerged in both the SSVEP and ERP signals at the suppressed location relative to all other locations. The early timing of these evoked modulations suggests that learned distractor suppression occurs at the initial stages of visual processing.
Learning modulates early encephalographic responses to distracting stimuli: a combined SSVEP and ERP study
Dock H. Duncan
Added on: 05-05-2025
Structural brain variability in schizophrenia
2025
University of Zurich, Zurich, Switzerland
The clinical diversity of schizophrenia is reflected by structural brain variability. In this meta- and mega-analysis, the structural heterogeneity in schizophrenia was analysed using the ENIGMA dataset of MRI-based brain measures from 22 international sites with over 6,000 individuals. Variability and mean values of five different brain measures - cortical thickness, cortical surface area, cortical folding index, subcortical volume, and fractional anisotropy - were examined in individuals with schizophrenia and healthy control subjects. The results showed that individuals with schizophrenia had greater variability in cortical thickness, surface area, subcortical volume, and fractional anisotropy, particularly in the frontotemporal and subcortical regions. This variability was linked to the severity of psychopathological symptoms, with patients often showing lower mean values in these areas. However, folding patterns in the right caudal anterior cingulate region were more uniform in individuals with schizophrenia. These patterns did not correlate with disease-related factors. The study suggests that while schizophrenia is associated with significant structural variability, the uniform folding in certain brain regions may indicate a less flexible brain development.
Estimating multimodal structural brain variability in schizophrenia spectrum disorders: A worldwide ENIGMA study
Philipp Homan
Added on: 03-25-2025
Ancient viral DNA in the human genome linked to neurodegenerative diseases
2025
King’s College London, London, United Kingdom
In this study, the researchers have discovered a link between ancient viral DNA within the human genome and the genetic risk for two significant neurodegenerative diseases: multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Human endogenous retroviruses (HERVs), remnants of ancient retroviral infections that are now fixed features within human DNA were the focus of the study. By using an advanced genomic technique, the researchers found specific HERV expression signatures, which indicate that viral elements within our DNA may influence the development of these neurodegenerative diseases. This is one of the first studies to pinpoint specific HERVs that are associated with disease susceptibility.
Ancient viral DNA in the human genome linked to neurodegenerative diseases
Rodrigo R.R. Duarte, Timothy R. Powell
Added on: 12-03-2024
Plasma protein signatures of loneliness associated with disease and mortality
2025
Fudan University, Shanghai, China
In this study, the proteomic signatures of social isolation and loneliness were characterized through proteome-wide association study and protein co-expression network analysis based on data from 42,062 participants across 2,920 plasma proteins in the UK Biobank. Proteins linked to these constructs were implicated in inflammation, antiviral responses and complement systems. More than half of these proteins were prospectively linked to cardiovascular disease, type 2 diabetes, stroke and mortality during a 14-year follow-up. Moreover, Mendelian randomization (MR) analysis suggested causal relationships from loneliness to five proteins, with two proteins further supported by colocalization. These MR-identified proteins were associated with blood biomarkers and brain regions involved in emotional and social processing and partly explained the connection between loneliness and health issues like cardiovascular disease, stroke, and mortality.
Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality
Wei Cheng, Jianfeng Feng, Barbara J. Sahakian
Added on: 02-26-2025
Dynamic cerebral organoids culture for developmental neurotoxicity
CompanyOctober 2024
University of North Texas, Denton, USA
Human brain organoids are a promising tool for assessing chemical effects on brain development, but traditional culture systems face challenges such as low throughput, poor reproducibility, insufficient maturity, and necrotic core formation. This study addressed these issues by using a dynamic pillar/perfusion plate system to culture cerebral organoids with improved proliferation and maturity through bidirectional flow. Organoids were exposed to ascorbic acid (non-toxic) and methylmercury (toxic) to evaluate developmental neurotoxicity (DNT). Ascorbic acid caused no changes, while methylmercury led to significant alterations in morphology and neural gene expression under dynamic conditions. Notably, methylmercury showed no adverse effects in static cultures, emphasizing the value of dynamic systems for DNT assessment. The pillar/perfusion plate system described in the study is commercially available from Bioprinting Laboratories Inc.
Dynamic culture of cerebral organoids using a pillar/perfusion plate for the assessment of developmental neurotoxicity
Moo-Yeal Lee
Added on: 02-11-2025
Modelling Parkinson’s disease in human dopaminergic neurons with α-synuclein and cytokines
October 2024
McGill University, Montreal, Canada
This study reveals that Lewy body (LB)-like inclusions, characteristic of Parkinson's disease (PD), can form in human dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) under specific conditions. LB formation occurs when neurons are exposed to α-synuclein preformed fibrils (PFFs) combined with an immune challenge or co-culture with activated microglia-like cells. Interferon-γ exposure impairs lysosomal function, contributing to LB formation. Knockdown of LAMP2 or knockout of GBA genes, combined with PFF administration, is sufficient for inclusion formation. The LB-like inclusions are membrane-bound, suggesting they may result from autophagy dysfunction. These findings indicate that immune-triggered lysosomal dysfunction may play a role in PD pathology development.
Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines
Peter S. McPherson, Armin Bayati
Added on: 12-03-2024
Neural processing of odors in the human brain
October 2024
RWTH Aachen University, Aachen, Germany(1)
University Hospital Bonn, Bonn, Germany(2)
University Hospital Bonn, Bonn, Germany(2)
This study involved patients who had been permanently implanted with electrodes in various areas of the brain (piriform cortex, amygdala, hippocampus) due to drug-resistant epilepsy. They were presented with odours while the activity of individual neurons in the brain regions was recorded at the same time. The results revealed that neurons in these areas fire in response to specific odours, encoding their identity. Repeated exposure to the same odour led to a reduction in neuron activity, highlighting central repetition suppression and habituation. Each brain region played a unique role in odour processing: the amygdala encoded emotional responses to odours, the hippocampus predicted odour identification performance, and the piriform cortex encoded the chemical structure of smells. Interestingly, some neurons also responded to both odours and images, indicating a connection between different sensory modalities. These findings offer new insights into how odours are processed in the human brain and how distinct brain regions contribute to this complex sensory experience.
Single-neuron representations of odours in the human brain
Marc Spehr(1), Florian Mormann(2)
Added on: 11-20-2024
Neural representation of „zero“ in the human brain
October 2024
University of Bonn Medical Center, Bonn, Germany(1)
University of Tübingen, Tübingen, Germany(2)
University of Tübingen, Tübingen, Germany(2)
This study investigated how the number „zero“ is processed in the human brain. To this end, single-neuron recordings were conducted in patients who had electrodes implanted in their brains as part of preoperative epilepsy monitoring. The recordings were taken during a number judgment task ("parity judgment task"), where participants had to decide whether a number was even or odd. The number “zero” was presented in two formats: symbolic (Arabic numeral “0”) and nonsymbolic (empty set of dots). It was found that the brain responded differently to symbolic and nonsymbolic representations of zero. In the nonsymbolic format, there was a difference in neuronal responses to small numbers compared to zero. In contrast, the symbolic zero was processed along the number line in the same way as other small numbers.
Single-neuron representation of nonsymbolic and symbolic number zero in the human medial temporal lobe
Florian Mormann(1), Andreas Nieder(2)
Added on: 03-04-2025
Glia-enriched brain organoids for modelling multiple sclerosis
2024
IRCCS San Raffaele Scientific Institute, Milano, Italy
The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. Here, a single transcription factor (SOX10)-based protocol was applied to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia that spatially and temporally overlap, allowing functional crosstalk among the different cell types.
Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimicked macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to find compounds tackling inflammatory demyelination and neurodegeneration.
A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis
Martina Absinta
Added on: 12-10-2024
iPSC-derived 3D neural models reveal pathomechanisms of Cockayne Syndrome B
2024
IUF – Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which—through largely unknown mechanisms—can affect the brain. It clinically presents with microcephaly, intellectual disability and demyelination. In this study, human induced pluripotent stem cell (hiPSC)-derived neural 3D models were generated from CSB patient-derived and control lines in order to understand the three major neuropathological phenotypes. In the models, CSB deficiency was shown to be associated with (i) impaired cell migration due to defective autophagy as an explanation for clinical microcephaly (ii) altered neuronal network functionality and neurotransmitter GABA levels, which might be the cause of intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of demyelination. Both impaired migration and oligodendrocyte maturation could be partially rescued by pharmacological histone deacetylase (HDAC) inhibition.
HiPSC‑derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B
Katharina Koch
Added on: 11-06-2024
Mutant huntingtin impairs neurodevelopment in brain organoids
2024
Heinrich Heine University, Düsseldorf, Germany(1)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany(2)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany(2)
Huntington’s disease (HD) is caused by the expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT). This study investigated how the mutant HTT (mHTT) affects early human brain development using brain organoids derived from genetically engineered induced pluripotent stem cells (iPSCs) with inserted or removed poly-Q in the HTT gene. It was observed that mHTT disrupts neural progenitor organization and impairs the development of cerebral organoids. RNA sequencing and proteomic analyses identified CHCHD2 as a key dysregulated transcription factor in the mHTT condition, leading to abnormal mitochondrial morpho-dynamics. Overexpression of CHCHD2 reverted mitochondrial dysregulartion, and removing the poly-Q tract was able to normalize CHCHD2 levels, correcting mitochondrial defects. These findings suggest that mHTT-induced neurodevelopmental defects are closely linked to mitochondrial dysfunction, and that CHCHD2 could be a potential therapeutic target for early intervention in HD.
Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure
Alessandro Prigione(1), Jakob J. Metzger(2)
Added on: 03-24-2025
Self-assembling 3D vessel-on-chip model with hiPSC-derived astrocytes
2024
Leiden University Medical Centre, Leiden, Netherlands
Functionality of the blood-brain barrier (BBB) relies on the interaction between endothelial cells (ECs), pericytes, and astrocytes to regulate molecule transport within the central nervous system. Most experimental models for the BBB rely on freshly isolated primary brain cells. Here, human induced pluripotent stem cells (hiPSCs) as a cellular source for astrocytes in a 3D vessel-on-chip (VoC) model were explored. Self-organized microvascular networks were formed by combining hiPSC-derived ECs, human brain vascular pericytes, and hiPSC-derived astrocytes within a fibrin hydrogel. The hiPSC-ECs and pericytes showed close interactions, but, somewhat unexpectedly, addition of astrocytes disrupted microvascular network formation. However, continuous fluid perfusion or activation of cyclic AMP (cAMP) signalling rescued the vascular organization and decreased vascular permeability. Nevertheless, astrocytes did not affect the expression of proteins related to junction formation, transport, or extracellular matrix, indicating that, despite other claims, hiPSC-derived ECs do not entirely acquire a BBB-like identity in the 3D VoC model.
Self-assembling 3D vessel-on-chip model with hiPSC-derived astrocytes
Valeria V. Orlova
Added on: 04-28-2025
Brain Chimeroids reveal individual susceptibility to neurotoxic triggers
2024
Harvard University, Cambridge, USA
Genetic variation among individuals influences disease susceptibility and progression. Studying human brain differences in normal and disease states is challenging due to a lack of accurate cellular models and scalable systems to represent multiple people. This study introduces human brain "Chimeroids," a reproducible, multidonor cortical organoid model created by co-developing cells from multiple donors within a single organoid. By reaggregating cells from individual donor organoids at the neural stem or progenitor cell stage, each donor's cells contribute fully to cerebral cortex lineages, even with differing growth biases. Chimeroids were used to study variability in response to neurotoxic agents like ethanol and valproic acid, revealing individual differences in cell type susceptibility and molecular effects. This model highlights genetic background as a factor in neurotoxin sensitivity and establishes Chimeroids as a scalable tool for studying brain development and disease across individuals.
Brain Chimeroids reveal individual susceptibility to neurotoxic triggers
Paola Arlotta
Added on: 11-07-2024
Hindbrain organoids for drug screening for the treatment of neuropsychiatric symptoms in Alzheimer's disease
2024
Johns Hopkins School of Medicine, Baltimore, USA
Almost all Alzheimer's disease (AD) patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. In this study, human peripheral blood mononuclear cells (PBMCs) from healthy volunteers and AD patient with or without NPS were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in serotonin levels before and after treatment with escitalopram were dose-dependent and variable across patients.
The authors propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.
iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric symptoms in Alzheimer’s disease
Vasiliki Mahairaki
Added on: 12-10-2024
Modelling blood-brain barrier and cerebral cavernous malformations with organoids
2024
Cincinnati Children's Hospital Medical Center, Cincinnati, USA(1)
Mayo Clinic College of Medicine and Science, Rochester, USA(2)
University of California, San Diego, USA(3)
Mayo Clinic College of Medicine and Science, Rochester, USA(2)
University of California, San Diego, USA(3)
The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, hBBB assembloids were constructed from brain and blood vessel organoids derived from human pluripotent stem cells. The acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics was validated and an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids was discovered. Using patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), it could be found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, CCM-related molecular and cellular alterations were uncovered. Taken together, hBBB assembloids that mimic the core properties of the hBBB were reported and a potentially underlying cause of CCMs was identified.
Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids
Ziyuan Guo(1), L. Frank Huang(2), Sheng Zhong(3)
Added on: 06-24-2024
New biomarker for asymptomatic stages of Alzheimer’s disease
2024
University of Barcelona, Barcelona, Spain
Clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. Presently, diagnosis at asymptomatic stages of Alzheimer's disease (AD) remains a challenge since it can only be made at autopsy according to Braak NFT staging. Achieving the objective of detecting AD at early stages would allow possible therapies to be addressed before the onset of cognitive impairment. Many studies have determined that the expression pattern of some miRNAs is dysregulated in AD patients, but to date, none has been correlated with downregulated expression of cellular prion protein (PrPC) during disease progression. That is why, cross studies of miRNAs up-regulated in AD with in silico identification of potential miRNAs-binding to 3′UTR of human PRNP gene were conducted. In this study, miR-519a-3p was selected for analyses. In vitro experiments were carried out to validate miR-519a-3p target on 3′UTR-PRN, and to analyze the levels of PrPC expression after using of mimic technology in cell culture. In order to analyse miR-519a-3p expression in human cerebral samples of AD at different stages of disease evolution, RT-qPCR was performed. Additionally, samples of other neurodegenerative diseases such as other non-AD tauopathies and several synucleinopathies were included in the study. The results showed that miR-519a-3p overlaps with PRNP 3′UTR in vitro and promotes downregulation of PrPC. Moreover, miR-519a-3p was found to be up-regulated exclusively in AD samples from stage I to VI, suggesting its potential use as a novel label of preclinical stages of the disease.
miR-519a-3p, found to regulate cellular prion protein during Alzheimer's disease pathogenesis, as a biomarker of asymptomatic stages
Rosalina Gavín
Added on: 06-24-2024
Personalized brain circuit scores identify distinct biotypes in depression and anxiety
2024
Stanford University School of Medicine, Stanford, USA
There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or ‘biotypes’ to enable stratification of patients with depression and anxiety. Here, task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol across multiple studies in patients with depression and anxiety when treatment free and after randomization to pharmacotherapy or behavioural therapy was used. From these patients, personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy were derived. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity, and activation and connectivity elicited by emotional and cognitive tasks. The six biotypes showed consistency with the theoretical taxonomy in this study, and were distinguished by symptoms, behavioural performance, and response to pharmacotherapy as well as behavioural therapy. The results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry.
Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety
Leanne M. Williams
Added on: 07-29-2024
Five HERV expression signatures linked to psychiatric disorders
2024
King’s College London, London, United Kingdom
Human endogenous retroviruses (HERVs) are repetitive elements previously implicated in major psychiatric conditions, but their role in aetiology remains unclear. Here, specialised transcriptome-wide association studies were performed that consider HERV expression quantified to precise genomic locations, using RNA sequencing and genetic data from 792 post-mortem brain samples. In Europeans, 1238 HERVs with expression regulated in cis could be identified, of which 26 represent expression signals associated with psychiatric disorders, with ten being conditionally independent of neighbouring expression signals. Of these, five are additionally significant in fine-mapping analyses and thus are considered high confidence risk HERVs. These include two HERV expression signatures specific to schizophrenia risk, one shared between schizophrenia and bipolar disorder, and one specific to major depressive disorder. No robust signatures could be identified for autism spectrum conditions or attention deficit hyperactivity disorder in Europeans, or for any psychiatric trait in other ancestries, although this is likely a result of relatively limited statistical power. Ultimately, this study highlights extensive HERV expression and regulation in the adult cortex, including in association with psychiatric disorder risk, therefore providing a rationale for exploring neurological HERV expression in complex neuropsychiatric traits.
Integrating human endogenous retroviruses into transcriptome-wide association studies highlights novel risk factors for major psychiatric conditions
Timothy R. Powell, Rodrigo R. R. Duarte
Added on: 06-24-2024
Isolating nerve cell precursors from dental pulp stem cells
2024
Queens University Belfast, Belfast, United Kingdom
Dental pulp stem cells (DPSCs) contain a diverse mix of stem cells with various potential uses, but this diversity can be challenging for research and clinical applications. This study aimed to isolate and study a specific type of nerve cell precursor from human DPSCs. The researchers used a specialized sorting technique to isolate these precursor cells from dental pulp samples from three human donors. They then examined the cells' characteristics and ability to develop into mature nerve cells. The isolated cells showed features of early-stage nerve cells and could be further developed into more mature nerve cells in laboratory conditions. These cells demonstrated functional properties similar to nerve cells, such as responding to certain chemicals and showing electrical activity. Overall, this study shows that dental pulp contains nerve cell precursors that can be effectively isolated and potentially used for further research or medical applications.
Immunological isolation and characterization of neuronal progenitors from human dental pulp: A laboratory-based investigation
Ikhlas El Karim
Added on: 12-20-2024
3D bioprinting of human neural tissues with functional connectivity
2024
University of Wisconsin-Madison, Madison, USA
Probing how human neural networks operate is hindered by the lack of reliable human neural tissues amenable to the dynamic functional assessment of neural circuits. Here, a 3D bioprinting platform was developed to assemble tissues with defined human neural cell types in a desired dimension using a commercial bioprinter.
The printed neuronal progenitors differentiated into neurons and formed functional neural circuits within and between tissue layers with specificity within weeks, evidenced by the cortical-to-striatal projection, spontaneous synaptic currents, and synaptic response to neuronal excitation. Printed astrocyte progenitors developed into mature astrocytes with elaborated processes and formed functional neuron-astrocyte networks, indicated by calcium flux and glutamate uptake in response to neuronal excitation under physiological and pathological conditions. These designed human neural tissues will likely be useful for understanding the wiring of human neural networks, modelling pathological processes, and serving as platforms for drug testing.
3D bioprinting of human neural tissues with functional connectivity
Su-Chun Zhang
Added on: 12-10-2024
Blood test to predict pathological brain activity in psychiatric and neurological diseases
2024
Johns Hopkins School of Medicine, Baltimore, USA
In the present study, researchers investigate the potential of extracellular vesicle (EV) mRNAs as tissue-specific biomarkers for detecting pathological brain activities that are associated with the occurrence of postpartum depression (PPD) and other psychiatric or neurological diseases. The experimental approach builds on previous results in which aberrant EV communication was observed in the blood of pregnant women with subsequent PPD. This suggests that analysis of EV mRNA by a simple blood test can be used to predict pathological organ changes (particularly in difficult-to-reach organs such as the brain). In addition to the use of publicly available big data sets, the blood samples of the study participants form the basis of the following studies. In order to prove that EV mRNA can be validly assigned to its tissue of origin, the researchers first examined a human model of the placenta using bioinformatic gene expression analysis. 23 placenta-specific biomarkers were identified that only appeared in the blood of pregnant women with subsequent PPD. The researchers then examined EV communication in specially developed mini-brains derived from human stem cells. The analysis detected 13 biomarkers in the brain-specific, female transcripts that were associated with the occurrence of PPD. In addition, in further series of tests, increased gene expression patterns in brain-specific EV mRNAs were observed, which are associated with psychiatric/neurological diseases such as schizophrenia or epilepsy. In summary, the results of the study demonstrate the high potential of a simple blood test, as a non-invasive method, for assessing specific organ functionality, which can help to improve the prevention and treatment of psychiatric and neurological diseases.
Blood extracellular vesicles carrying brain-specific mRNAs are potential biomarkers for detecting gene expression changes in the female brain
Sarven Sabunciyan
Added on: 03-13-2024
Neurodevelopmental defects in organoids with ANG mutation
2024
University of Bath, Bath, United Kingdom
Mutations in Angiogenin (ANG) and TARDBP are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. The researchers obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. They reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress were investigated. Multiple striking neurodevelopmental defects were observed. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. The findings may indicate that subtle developmental defects play a role in disease susceptibility or onset.
Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin
Vasanta Subramanian
Added on: 04-02-2024
A new AI approach using electrical stimulation of organoids
December 2023
Indiana University Bloomington, Bloomington, USA
To overcome the limitations of today's artificial intelligence (AI), one could use computer hardware that is based on the structure and function of the brain. However, silicon chips designed to mimic the brain cannot yet fully imitate brain functions. This study presents a new hardware approach for AI that utilizes the adaptive processing of information in biological networks of a brain organoid. In this approach, called Brainoware, information processing occurs by sending data to and receiving data from a brain organoid. For this, a high-density multielectrode array is used. Through the targeted application of electrical impulses, certain dynamic processes and a kind of short-term memory are imitated. The system also learns independently from training data by changing the connections in the organoid. The practical applicability of this method is demonstrated by using it for speech recognition and the prediction of complex equations in a special computational model.
Brain organoid reservoir computing for artificial intelligence
Feng Guo
Added on: 04-30-2025
Association between Helicobacter pylori and Alzheimer's disease
December 2023
McGill University, Montreal, Canada
This population-based study assessed whether clinically apparent Helicobacter pylori infection is associated with the risk of Alzheimer's disease (AD).
Therefore, a population-based cohort of all dementia-free subjects in the United Kingdom’s Clinical Practice Research Datalink, which contains anonymized medical records from general practitioners including medical diagnoses and procedures, was used. Within the study cohort, all cases with a first-time diagnosis of AD were identified. Each AD case was matched to up to 40 AD-free controls. All cases and controls were screened for clinically apparent Helicobacter pylori infection and salmonellosis as a negative control.
Among 4,262,092 dementia-free subjects, 40,455 developed AD within 11 years. Clinically apparent Helicobacter pylori infection increased the risk to develop Alzheimer's disease by 11 % in individuals aged ≥50 years.
Clinically apparent Helicobacter pylori infection and the risk of incident Alzheimer’s disease: A population-based nested case-control study
Paul Brassard
Added on: 01-13-2024
Midbrain organoids to investigate the cause of Parkinson's disease
December 2023
University of Luxembourg, Esch-sur-Alzette, Luxembourg
The mechanisms underlying the aetiology of Parkinson's disease are still only partially understood. Recent evidence suggests that early defects in neurodevelopment may play a role in cellular susceptibility to neurodegeneration. To investigate the early developmental contribution of GBA mutations in Parkinson's patients, iPSCs carrying a heterozygous N370S mutation in the GBA gene were used. Patient-specific midbrain organoids exhibited GBA-PD-related phenotypes, such as a reduction in GCase activity, impaired autophagy and mitochondrial dysfunction. Genome-scale metabolic modelling (GEM) predicted changes in lipid metabolism, which were validated by lipidome analysis and showed significant differences in the lipidome of GBA-PD. In addition, patient-specific midbrain organoids showed a decrease in the number and complexity of dopaminergic neurons. This was accompanied by an increase in the neural progenitor population, which showed signs of oxidative stress-induced damage and premature cellular senescence. These results shed light on how GBA mutations can lead to neurodevelopmental defects and thus favour the development of Parkinson's disease.
Impaired neuron differentiation in GBA-associated Parkinson’s disease is linked to cell cycle defects in organoids
Jens C. Schwamborn
Added on: 02-19-2024
AI model reveals links between structural and functional brain characteristics
November 2023
University of Cambridge, Cambridge, United Kingdom
In this study, the researchers have demonstrated that putting physical constrains on an artificially intelligent system, similarly to how the human brain develops and functions within physical and biological constraints, enables it to develop features of complex organisms’ brains to solve problems. They created an artificial system aimed at modelling a simplified version of the brain and applied physical constraints. The system developed some key characteristics like those found in human brains. This AI system may start to uncover how these constraints shape differences between people’s brains and impact the differences observed in people experiencing cognitive or mental health difficulties.
Spatially embedded recurrent neural networks reveal widespread links between structural and functional neuroscience findings
Danyal Akarca, Jascha Achterberg
Added on: 04-02-2024
Cardiac function influences motor excitability of the autonomic nervous system
November 2023
Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
In the present study, the influence of cardiac function on motor excitability was examined. 36 healthy white subjects aged between 18 and 40 years took part in the study. In the first phase of the experiment, transcranial magnetic stimulation (TMS) was performed on participants in several blocks. Changes in cortical and corticospinal excitability were recorded using electroencephalography (EEG) and electromyography (EMG). At the same time, cardiac activity was monitored using electrocardiography (ECG). Fluctuations in motor excitability were analysed and assessed across the systolic and diastolic phases of cardiac activity. The results show that cortical and corticospinal excitability reached the highest levels during cardiac contraction and was enhanced following stronger neuronal responses to heartbeats. In a second phase of the experiment, the same parameters were collected while the subjects had to solve a pinch motor task. It was also observed here that hand muscle activity and the associated desynchronization of sensorimotor oscillations were more pronounced during systole than during the relaxation phase of the heart. In summary, the results of the study indicate that, in contrast to previous findings from previous studies on somatosensory perception, systolic cardiac activity appears to have a positive or supportive effect on motor excitability. The results may help to reevaluate and optimize TMS as a therapeutic application in epilepsy, depression or stroke patients.
Cardiac activity impacts cortical motor excitability
Esra Al
Added on: 11-30-2023
Brain metastasis-on-a-chip
October 2023
Seoul National University, Seoul, South Korea
The human brain choroid plexus (ChP) is a secretory tissue separating blood from the crerebrospinal fluid (CSF) thereby functioning as the blood-CSF barrier.
In this study, the ChP structure is recapitulated by developing a microfluidic chip which is used to culture human ChP cells. The brain extracellular matrix is mimicked by using a hydrogel and CSF flow dynamics by rocking the system. The use of the ChP-on-a-chip in drug screening is demonstrated by observing physiologically relevant drug responses from breast cancer cells that had spread in the ChP. ChP immune responses are also recapitulated, as demonstrated by the motility and cytotoxic effects of macrophages.
The human ChP-on-a-chip will facilitate the elucidation of ChP pathophysiology and support the development of therapeutics to treat cancers that have metastasized into the ChP.
Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis
Noo Li Jeon
Added on: 09-11-2023
Development of spatially organized brain organoids
2023
Kyoto University Institute for Advanced Study, Kyoto, Japan(1)
University of California, Irvine, USA(2)
University of California, Irvine, USA(2)
In human brain development, groups of brain cells act as “signalling centres” by creating gradients of certain molecules to guide brain organization. In this study, a brain organoid-on-a-chip platform is demonstrated, which generates signalling gradients that facilitate the induction of structured forebrain organoids.
To allow the directed development of distinct brain regions in organoids derived from induced pluripotent stem cells (iPSC), a multi-layered microfluidic device was developed. The device is able to generate four different concentration gradients in a culture chamber, while simultaneously avoiding high shear stress. Within the cultivation chamber, forebrain organoids were embedded in hydrogels and exposed to an extracellular smoothened agonist (SAG, a molecule involved in brain development) concentration gradient. The resulting organoids exhibited topographically organized domains, including cortical, lateral, and/or medial transient fetal brain structures in a precise spatial organization of ventral and dorsal domains.
These structured organoids represent a more complete mimic of the human brain and will be useful in evaluating neurodevelopment and investigating diseases.
Brain organoid-on-a-chip to create multiple domains in forebrain organoids
Ken-ichiro Kamei(1), Momoko Watanabe(2)
Added on: 09-29-2023
Optimization of brain model cellular composition
2023
Bloomberg School of Public Health Johns Hopkins University, Baltimore, USA
Most brain organoid models are predominantly composed of different neuronal types, with a smaller percentage of glial cells present compared to in vivo conditions. The aim of this study was to expand the population of astrocytes and oligodendrocytes by using an optimized and chemically defined culture medium.
Brain models were differentiated from two induced pluripotent stem cell (iPSC) and two embryonic stem cell lines. It was found that by use of the optimized medium, astrocytes not only increased in number but also changed in morphology, more closely recapitulating primary culture astrocytes.
The optimized culture conditions have the potential to significantly improve microphysiological brain models for the study of neurological diseases and drug discovery.
A novel approach to increase glial cell populations in brain microphysiological systems
Lena Smirnova
Added on: 12-09-2023
Amyotrophic Lateral Sclerosis (ALS)-on-a-chip
2023
University of Central Florida, Research Parkway, USA
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to death within 2–5 years of diagnosis. In this study, it was investigated how improving of human skeletal muscle (hSKM) viability and function affects the integrity of neuromuscular junctions (NMJ) in ALS.
Therefore, an ALS NMJ human-on-a-chip model was developed using patient-derived induced pluripotent stem cells (iPSCs) differentiated into motoneurons and myoblasts. The model was used to study the effect of hSKM-specific creatine treatment on clinically relevant functional ALS NMJ parameters. Results indicated comparatively enhanced NMJ numbers, and stability, as well as reduced fatigue index, across creatine-treated systems.
The study demonstrates the utilization of organ-on-a-chip technology for recapitulating complex human diseases like ALS and its applicability for drug toxicological and efficacy screening.
The effect of skeletal muscle-specific creatine treatment on ALS NMJ integrity and function
James J. Hickman
Added on: 10-16-2023
Organoid model for traumatic brain injury in humans
2023
University of Pittsburgh Medical Center, Pittsburgh, USA
Creating an environment, that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain. Here, a novel approach to emulate mild and moderate traumatic brain injury (TBI) was proposed using hCOs that undergo strain rates indicative of TBI. The researchers subjected the hCOs to mild and moderate loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, a steeper ascent in calcium signalling was shown as higher loading conditions on the organoids were imposed. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of traumatic brain injury in humans.
Characterization of neural mechanotransduction response in human traumatic brain injury organoid model
Pascal O. Zinn
Added on: 09-20-2023
Improved brain organoid formation by synthetic extracellular matrices
2023
University of Michigan, Ann Arbor, USA
Although brain organoids mimic the human brain's cell-to-cell network interactions, they generally fail to faithfully recapitulate cell-to-matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell-to-matrix interactions to developing brain organoids.
Brain organoids were generated using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. These brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment.
The interstitial matrix-mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long-term culture, which promoted large-volume organoids containing over 250 μL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF.
Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models.
Engineered extracellular matrices facilitate brain organoids from human pluripotent stem cells
Joerg Lahann, Eva L. Feldman
Added on: 07-20-2023
Effect of walnut consumption on neuropsychological development
2023
Hospital Universitari Sant Joan de Reus, Reus, Spain
The aim of this study was to investigate the potential benefit of consuming walnuts, which are a source of omega-3 alpha-linolenic acid (ALA), on adolescent neurodevelopment.
Therefore, 771 healthy adolescents aged between 11 and 16 years were included in this study. All participants were instructed to follow general healthy eating recommendations and were randomly assigned to one of two groups: the intervention group was instructed to include 30 g of walnuts per day into their diet, while the control group got no specific recommendation. Multiple primary endpoints concerning neuropsychological (including working memory, attention, and fluid intelligence) and behavioural (socioemotional and attention deficit hyperactivity disorder (ADHD) symptoms) development were assessed at baseline and after 6 months of intervention.
The results of the study suggest that eating walnuts for 6 months did not improve the neuropsychological function of healthy adolescents. However, improved sustained attention and fluid intelligence, describing the capacity for logical reasoning, were observed in participants who better complied with the walnut intervention.
Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial
Jordi Julvez
Added on: 07-03-2023
Influence of dopamine on cognitive function
2023
Technische Universität Dresden, Dresden, Germany
The aim of this functional brain imaging study, was to investigate potential effects of a placebo-controlled L- DOPA intervention on spatial learning and memory in healthy young and older adults at the behavioral and brain level.
Functional neuroimaging was performed with187 volunteers. Participants attended three fMRI sessions, one behavioral and two pharmaco-fMRI, in which they either received L-DOPA or a placebo before performing a computerized spatial navigation task.
The results suggest that increasing dopamine availability improves hippocampus-dependent place learning in some older adults
Dopamine differentially modulates medial temporal lobe activity and behavior during spatial navigation in young and older adults
Christian Baeuchl
Added on: 04-24-2023
Obstructive sleep apnea may directly cause early cognitive decline
2023
King's College London, London, United Kingdom
Obstructive sleep apnoea (OSA) is a multisystem, debilitating, chronic disorder of breathing during sleep, resulting in a relatively consistent pattern of cognitive deficits. More recently, it has been argued that those cognitive deficits, especially in middle-aged patients, may be driven by cardiovascular and metabolic comorbidities, rather than by distinct OSA-processes, such as are for example ensuing nocturnal intermittent hypoxaemia, oxidative stress, neuroinflammation, and sleep fragmentation. Here, the researchers analysed the cognitive performance in a group of 27 middle-aged male patients with untreated OSA, who had no concomitant comorbidities, compared with seven matched controls. The patient cohort exhibited poorer executive-functioning, visuospatial memory, and deficits in vigilance sustained attention, psychomotor and impulse control. Effects on social cognition were also reported in this group of male, middle-aged OSA patients. These findings suggest that distinct, OSA-driven processes may be sufficient for cognitive changes to occur as early as in middle age, in otherwise healthy individuals.
Distinct cognitive changes in male patients with obstructive sleep apnoea without co-morbidities
Ivana Rosenzweig
Added on: 05-02-2023
Viral infectivity of enterovirus A71 studied in a human primary intestinal model
2023
University of Amsterdam, Amsterdam, Netherlands
Enterovirus A71 (EV-A71) can elicit a wide variety of human diseases such as hand, foot, and mouth disease and severe or fatal neurological complications. It is not clearly understood what determines the virulence and fitness of EV-A71. It has been observed that amino acid changes in the receptor binding protein, VP1, resulting in viral binding to heparan sulfate proteoglycans (HSPGs) may be important for the ability of EV-A71 to infect neuronal tissue. In this study, the researchers identified that the presence of glutamine, as opposed to glutamic acid, at VP1-145 is key for viral infection in a 2D human fetal intestinal model, consistent with previous findings in an airway organoid model. Moreover, pre-treatment of EV-A71 particles with low molecular weight heparin to block HSPG-binding significantly reduced the infectivity of two clinical EV-A71 isolates and viral mutants carrying glutamine at VP1-145. These data indicates that mutations in VP1 leading to HSPG-binding enhances viral replication in the human gut. The mutations resulting in increased production of viral particles at the primary replication site could lead to a higher risk of subsequent neuroinfection.
Amino acid variation at VP1-145 of enterovirus A71 determines the viral infectivity and receptor usage in a primary human intestinal model
Adithya Sridhar, Ikrame Aknouch
Added on: 07-18-2023
Blood–brain barrier (BBB)-on-a-chip for Alzheimer’s disease
2023
Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain
Here, the researchers developed a blood–brain barrier (BBB)-on-a-chip (BBB-oC) platform with a trans-endothelial electrical resistance (TEER) measurement system at a close distance to the barrier. The system characterization displayed a neurovascular network and the expression of tight junctions in the endothelium. It was used for the first time to evaluate the permeability performance of targeted gold nanorods for theranostics of Alzheimer’s disease. The BBB-oC with a novel TEER integrated setup was proven as a functional and throughput platform to evaluate the brain permeability performance of nanotherapeutics in a physiological environment with human cells.
BBB-on-a-chip with integrated micro-TEER for permeability evaluation of multi-functionalized gold nanorods against Alzheimer’s disease
Mònica Mir, Anna Lagunas
Added on: 04-24-2023
Cerebral organoids for multiple sclerosis variants research
2023
Tisch Multiple Sclerosis Research Center of New York, New York, USA
Multiple sclerosis is an inflammatory autoimmune disease in which the protective myelin layer of nerve cells is attacked and destroyed. Using patient-specific organoids (plus control organoids from healthy donors), all 3 main forms of MS (relapsing-remitting MS = RRMS, secondary progressive MS = SPMS, and primary progressive MS = PPMS) could be recapitulated. By this, the (possible) differences between the various forms of progression could also be investigated. These organoids revealed that in the MS forms, but especially in PPMS, the differentiation of oligodendrocytes is decreased compared to the healthy organoids, i.e. the cells responsible for building up myelin. Moreover, a lower expression of the cell cycle inhibitor p21 was found, which could be a possible therapeutic approach.
Cerebral organoids in primary progressive multiple sclerosis reveal stem cell and oligodendrocyte differentiation defect
Saud A. Sadiq
Added on: 04-12-2023
fMRI of sensorimotor activation of the thalamus
2023
Max Planck Institute for Biological Cybernetics, Tuebingen, Germany
This study aims to identify the sensorimotor nuclei of the thalamus of humans using functional magnetic resonance imaging (fMRI) by assessing blood oxygen level-dependent (BOLD) response during an active motor and a passive sensory stimulation.
Ten healthy volunteers participated in the study. In the active motor task, participants were instructed to tap their right fingers in an ordered fashion against the thumb. In the passive sensory stimulation, pressure was delivered to different fingers of the participants. fMRI allowed to identify nuclei activated in the different tasks.
The study provides insight into the function of individual thalamic nuclei in processing various input signals and corroborates the benefits of fMRI to investigate deeply located brain structures.
Functional mapping of sensorimotor activation in the human thalamus at 9.4 Tesla
Edyta Charyasz
Added on: 10-19-2023
Too much or too little sleep may be associated with infections
2023
University of Bergen, Bergen, Norway
There is emerging evidence that sleep problems and short sleep duration increase the risk of infection. The researchers aimed to assess whether chronic insomnia disorder, chronic sleep problems, sleep duration and circadian preference based on self-report were associated with the risk of infections and antibiotic use among patients visiting their general practitioner (GP). They conducted a cross-sectional study of 1,848 unselected patients in Norway visiting their GP in 2020. The risk of infection was 27% and 44% higher in patients sleeping <6 h and >9 h, respectively, compared to those sleeping 7–8 h. The risk was also increased in patients with chronic insomnia disorder or a chronic sleep problem. For antibiotic use, the risk was higher for patients sleeping <6 h, and for those with chronic insomnia disorder or a chronic sleep problem. These findings support the notion of a strong association between sleep and infection.
The association between self-reported sleep problems, infection, and antibiotic use in patients in general practice
Ingeborg Forthun
Added on: 05-02-2023
3D human co-culture to model neuron-astrocyte interactions in tauopathies
2023
Vrije Universiteit Amsterdam, Amsterdam, Netherlands
Intraneuronal tau aggregation is the major pathological feature of neurodegenerative tauopathies. To model the interaction between neurons and astrocytes in tauopathies, a 3D human neuron/astrocyte co-culture model was established here, containing homogeneous populations of hiPSC-derived neurons and primary human astrocytes in microtiter plate format. Using confocal, electron, and live microscopy, neurons in 3D coculture were shown to form pre- and postsynapses and exhibit spontaneous calcium transients within 4 weeks. Astrocytes in 3D co-culture exhibited a bipolar and stellate morphology with extensive processes enveloping neuronal somas, spatially aligned with axons and dendrites, and found perisynaptically. The complex morphology of astrocytes and interaction with neurons in 3D coculture mirrored that of the human brain, indicating the potential of the model to study physiological and pathological neuron-astrocyte interactions in vitro. In addition, the authors developed a method to introduce seed-independent intraneuronal tau aggregation in 3D co-culture, allowing the study of neuron-astrocyte interactions in early tau pathogenesis.
Overall, these data provide evidence for the utility of this rapid, miniaturized, and standardized 3D model for cell type-specific manipulations, such as intraneuronal pathology associated with neurodegenerative diseases.
A 3D human co-culture to model neuron-astrocyte interactions in tauopathies
Wiep Scheper
Added on: 04-27-2023
Characterization of NGLY1 patient-derived midbrain organoids
2023
National Institutes of Health (NIH), Bethesda, USA
NGLY1 deficiency is an extremely rare autosomal recessive inherited disease caused by mutations in the NGLY1 gene. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delays, motor dysfunction, and liver dysfunction. To better understand the pathogenesis of the disease and the neurological symptoms of NGLY1 deficiency, the researchers generated and characterized midbrain organoids using iPSCs from two patients with different disease-causing mutations and CRISPR-generated NGLY1 knockout iPSCs. NGLY1-deficient midbrain organoids were shown to exhibit altered neuronal development compared with a wild-type (WT) organoid. Both neuronal (TUJ1) and astrocytic glial fiber protein markers were reduced in midbrain organoids derived from NGLY1 patients, as was the neurotransmitter GABA. Interestingly, staining of the dopaminergic neuronal marker tyrosine hydroxylase showed a significant reduction in patient-derived iPSC organoids. These results provide a relevant NGLY1 disease model to investigate disease mechanisms and evaluate therapeutics to treat NGLY1 deficiency.
Generation and characterization of NGLY1 patient-derived midbrain organoids
Wei Zheng, Atena Farkhondeh
Added on: 03-14-2023
Cocaine addiction makes the brain age faster
2023
Heidelberg University, Mannheim, Germany
Cocaine use disorder (CUD) is characterized by a loss of control over cocaine intake and is associated with structural, functional, and molecular alterations in the human brain. At the molecular level, epigenetic alterations are hypothesized to contribute to the higher-level functional and structural brain changes observed in CUD. Here, the researchers investigated epigenome-wide DNA methylation (DNAm) signatures of CUD in human post-mortem brain tissue of 21 individuals with CUD and 21 individuals without a CUD diagnosis. They performed an epigenome-wide association study and analysed CUD-associated differentially methylated regions. The authors also investigated epigenetic age in CUD using epigenetic clocks for the assessment of biological age. The results from this study highlight that CUD is associated with epigenome-wide differences in DNAm levels, particularly related to synaptic signalling and neuroplasticity. The researchers found evidence that brain cells appear biologically ‘older’ in people with CUD, suggesting that these cells age faster than in people without substance use disorders.
DNA methylation in cocaine use disorder - An epigenome-wide approach in the human prefrontal cortex
Stephanie H. Witt
Added on: 05-02-2023
Effects of praise and flattery on the brain
2023
Tohoku University, Sendai, Japan
Both sincere praise and flattery are rewarding in different ways, but the various effects of these types of praise are not obvious. Here, the researchers examined the brain activity of participants who received sincere praise or flattery after performing a visual search task. Using neuroimaging, the researchers found different effects of praise. The activation of the part of the brain modulating reward and pleasure processing was higher when participants received sincere praise than when they received flattery. The scientists also observed a socio-emotional effect, based on the positive feedback conveyed by praise. Altogether, they found that the neural dynamics of the rewarding and socio-emotional effects of different types of praise differ.
Sincere praise and flattery: reward value and association with the praise-seeking trait
Shotaro Fujiwara
Added on: 05-02-2023
Exploring 4H leukodystrophy using patient samples
2023
Vrije Universiteit Amsterdam, Amsterdam, Netherlands
4H leukodystrophy is a rare genetic disorder usually characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. With the discovery that 4H is caused by mutations affecting RNA polymerase III, which is mainly involved in the transcription of small noncoding RNAs, patients with atypical presentations, mainly showing a neuronal phenotype, have also been identified. The pathomechanisms of 4H brain abnormalities are still unknown. The aim of this study was to identify cells and signaling pathways affected by 4H mutations.
RNA-seq analysis of induced pluripotent stem cell-derived cerebellar cells revealed several differentially expressed genes between 4H patients and control samples, including decreased ARX expression. This correlated with changes in interneurons in the primary tissue of 4H patients. In addition, cortical neurons derived from induced pluripotent stem cells from 4H patients had a decreased proportion of GABA-ergic synapses, which correlated with an increased neuronal network activity. Treatment of cultures with GABA antagonists resulted in a significant increase in neuronal network activity in control cells but not in 4H cells, also suggesting a lack of inhibitory activity in 4H. Myelination and maturation of oligodendrocytes in cultures with 4H neurons were normal, and treatment with the Sonic hedgehog agonist SAG did not improve neuronal phenotypes associated with 4H. Quantitative PCR analysis revealed increased expression of the parvalbumin interneuron marker ERBB4, suggesting that development rather than formation of interneurons may be affected in 4H.
Overall, these results suggest that interneurons, possibly parvalbumin interneurons, are involved in the disease mechanisms of 4H leukodystrophy.
Cortical interneuron development is affected in 4H leukodystrophy
Vivi M. Heine
Added on: 04-27-2023
Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish
2023
Johns Hopkins University, Baltimore, USA
Recent advances in human stem cell-derived brain organoids promise to replicate critical molecular and cellular aspects of learning and memory and possibly aspects of cognition in vitro, thereby, creating a novel scientific discipline called “organoid intelligence” (OI).
By presenting a collaborative program to implement the vision of a multidisciplinary field of OI, the authors aim to establish OI as a form of genuine biological computing that harnesses brain organoids using scientific and bioengineering advances in an ethically responsible manner. Standardized, 3D, myelinated brain organoids can now be produced with high cell density and enriched levels of glial cells and gene expression critical for learning. Integrated microfluidic perfusion systems can support scalable and durable culturing, and spatiotemporal chemical signalling. Novel 3D microelectrode arrays permit high-resolution spatiotemporal electrophysiological signalling and recording to explore the capacity of brain organoids to recapitulate the molecular mechanisms of learning and memory formation and, ultimately, their computational potential. Technologies that could enable novel biocomputing models via stimulus-response training and organoid-computer interfaces are in development.
The strategic development of OI as a scientific discipline combined with an embedded ethics approach to analyse the ethical aspects raised by OI research, may help facilitate the development of OI-based biocomputing systems that allow faster decision-making, continuous learning during tasks, and greater energy and data efficiency.
Organoid intelligence (OI): the new frontier in biocomputing and intelligence-in-a-dish
Thomas Hartung
Added on: 06-10-2024
Seasonal variation in sleep architecture
2023
Charité – Universitätsmedizin Berlin, Berlin, Germany
While short-term effects of artificial light on human sleep are increasingly being studied, reports on long-term effects induced by season are scarce. Assessments of subjective sleep length over the year suggest a substantially longer sleep period during winter. This retrospective study aimed to investigate seasonal variation in objective sleep measures in a cohort of patients living in an urban environment. A three-night polysomnography was performed on 188 patients with neuropsychiatric sleep disturbances. Measures of the diagnostic second nights were averaged per month and analysed over the year. Analyses showed seasonal changes in total sleep time, REM-sleep latency, REM-sleep duration, and slow-wave-sleep duration. Data suggest seasonal variation in sleep architecture even when living in an urban environment in patients with disturbed sleep. If replicated in a healthy population, this would provide first evidence for a need to adjust sleep habits to season.
Seasonality of human sleep: Polysomnographic data of a neuropsychiatric sleep clinic
Dieter Kunz
Added on: 05-02-2023
Genome-wide screening identifies genes for amyloid beta peptide toxicity
2023
Universitat Pompeu Fabra, Barcelona, Spain
Alzheimer’s disease (AD) is known to be caused by amyloid β-peptide (Aβ) misfolded into β-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aβ toxicity, the researchers carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aβ1–42. They identified 81 mammalian orthologous genes that enhance Aβ1–42 toxicity, while 157 were protective. The most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. In summary, the authors identified new enhancer and protective activities for Aβ toxicity and showed that SURF4 contributes to Aβ1–42 neurotoxicity by decreasing store-operated calcium channel (SOCE) activity.
A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity
Francisco J. Muñoz
Pol Picón-Pagès et al. International Journal of Molecular Sciences 2023 [68]
Drug Target Review [69]
Added on: 04-25-2023
Hormone replacement therapy for women at risk of Alzheimer’s
2023
Norwich Medical School, Norwich, United Kingdom
The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. Here, the researchers investigate the modulating role of APOE genotype and age at hormone replacement therapy (HRT) initiation on the heterogeneity in cognitive response to HRT. The analysis used baseline data from 1906 participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on various cognitive and MRI outcomes. HRT introduction is associated with improved delayed memory in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher lifetime risk of Alzheimer’s in this large at-risk population subgroup.
Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort
Rasha N. M. Saleh
Added on: 01-19-2023
Long-term deep meditation alters gut microbiota
2023
Shanghai Jiao Tong University School of Medicine, Shanghai, China
Advancements in research have confirmed that gut microbiota can influence health through the microbiota–gut–brain axis. Meditation, as an inner mental exercise, can positively impact the regulation of an individual’s physical and mental health. The aim of this study is to investigate the effects of long-term deep meditation on the gut microbiome structure. 16S rRNA gene sequencing was performed on faecal samples of 56 Tibetan Buddhist monks and neighbouring residents (controls), and subsequent analysis was employed to identify differential intestinal microbial communities between the two groups. In addition, the researchers evaluated biochemical indices in the plasma. The gut microbiota composition differed between the monks and control subjects. The microbiota enriched in monks was associated with a reduced risk of anxiety, depression and cardiovascular disease and could enhance immune function. Overall, these results suggest that meditation plays a positive role in psychosomatic conditions and well-being.
Alteration of faecal microbiota balance related to long-term deep meditation
Jinghong Chen, Donghong Cui
Added on: 01-19-2023
Oligodendrogenesis and myelination in a brain microphysiological system
2023
Johns Hopkins University, Baltimore, USA
Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), can be differentiated from human induced pluripotent stem cells (hiPSCs), but in vitro modelling of axon myelination in human cells remains challenging. Brain microphysiological systems (bMPS) such as organoids provide an ideal system for studying this process, as OLs differentiate in a more in vivo-like environment, surrounded by neurons and astrocytes that support axon myelination.
Here, the benefits of CRISPR/Cas9 technology were taken advantage of to use reverse transfection to tag the OLs marker proteolipid protein 1 (PLP1) with a fluorescent fusion tag. By differentiating the resulting cell lines in the 3D brain model, the reliability, specificity, and function of the labelled PLP protein were verified and different stages of oligodendrogenesis were followed. Treatment of bMPS with cuprizone resulted in changes in the percentage of labelled cells.
This work demonstrates an efficient method to generate tagged hiPSC lines and the description of a new 3D model to study OL differentiation, migration, and maturation both during in vitro neurodevelopment and in response to environmental chemicals or disease-related stressors.
Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system
Lena Smirnova
Added on: 03-14-2023
‘Loosening of associations’ found in schizophrenia
December 2022
Tokyo Medical and Dental University, Tokyo, Japan
Schizophrenia is a mental illness that presents with thought disorders including delusions and disorganized speech. Thought disorders have been regarded as a consequence of the loosening of associations between semantic concepts. To evaluate how aberrant semantic connections are expressed through brain activity, the researchers characterized large-scale network structures of concept representations using functional magnetic resonance imaging (fMRI). They quantified various concept representations in patients’ brains from fMRI activity evoked by movie scenes using encoding modelling and subsequently constructing semantic brain networks. The results provide pathophysiological evidence for the loosening of associations in schizophrenia. This method represents a promising approach for understanding the neural basis of altered or creative inner experiences of individuals with mental illness or exceptional abilities, respectively.
Disorganization of semantic brain networks in schizophrenia revealed by fMRI
Hidehiko Takahashi
Added on: 01-19-2023
Cerebrospinal fluid immune dysregulation during brain aging and cognitive impairment
December 2022
Northwestern University Feinberg School of Medicine, Chicago, USA
Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with ageing or neurodegenerative disease. Here single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years was performed. An upregulation of lipid transport genes in monocytes with age was uncovered. Then this cohort was compared with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signalling to CD8 T cells. Additionally, the authors uncovered CXCL16-CXCR6 signalling as a potential mechanism of antigen-specific T cell entry into the intrathecal space of patients with CI. These findings could be used to improve anti-inflammatory therapeutics or to estimate levels of neuroinflammation in cognitively impaired patients.
Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment
David Gate
Added on: 01-30-2023
Deep brain stimulation for treatment of Alzheimer´s disease
December 2022
Charité – Universitätsmedizin Berlin, Berlin, Germany
Within this study, deep brain stimulation (DBS) is examined as an investigational treatment for patients with mild Alzheimer’s disease. In particular, the electrode placement was investigated and optimized with regard to the improvement of the cognitive function of the involved patients.
To investigate this, data obtained from 46 patients treated with DBS at seven international centres were used. The optimal stimulation site was identified using structural and functional connectivity data, as well as modulation of brain networks related to memory.
Findings were robust and could define an optimal target for Alzheimer’s Disease treatment that could refine DBS surgery and programming.
Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer’s disease
Andreas Horn
Added on: 01-06-2023
Influence of glucocorticoids on microglia development
December 2022
University College London Institute of Neurology, London, United Kingdom
Prenatal exposure to glucocorticoids (GC) results in a higher risk of psychiatric and neurodevelopmental disorders in later life. In this study, induced pluripotent stem cells (iPSCs) were generated from fibroblasts derived from patients and healthy individuals. iPSCs were exposed to GC during early differentiation into microglia, and it was examined how this exposure affected the microglial phenotype using RNA-seq analyses and functional assays.
The in vitro model allows the investigation of the responses of microglia in the pathogenesis of prenatal GC- exposure-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autism spectrum disorder.
Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN- response pathway activation and senescence in differentiated microglia; an early life stress model
Thomas M. Piers, Jennifer M. Pocock
Added on: 10-26-2023
Investigation of neuroinvasion by SARS-CoV-2
December 2022
KU Leuven, Leuven, Belgium(1)
Max Planck Research Unit for Neurogenetics, Frankfurt, Germany(2)
Max Planck Research Unit for Neurogenetics, Frankfurt, Germany(2)
In this study, it was investigated if SARS-CoV-2 could take a direct and short route from the nose into the brain. Therefore, tissue, blood, and cerebrospinal fluid samples from COVID-19 patients who died during the acute phase of infection and were infected with the Delta, Omicron BA.1, or Omicron BA.2 variants were used. Infected cells were visualized, and ongoing viral replication and extracellular virions were investigated.
No evidence was found for viral invasion of the parenchyma of the olfactory bulb and the frontal lobe of the brain. Instead, perineurial olfactory nerve fibroblasts were found to form a hitherto unrecognized anatomical barrier against SARS-CoV-2 virions.
Anatomical barriers against SARS-CoV-2 neuroinvasion at vulnerable interfaces visualized in deceased COVID-19 patients
Laura Van Gerven(1), Peter Mombaerts(2)
Added on: 01-09-2023
Senescence in aged human neurons associated with Alzheimer’s disease
December 2022
The Salk Institute for Biological Studies, La Jolla, USA(1)
University of California, La Jolla, USA(2)
University of California, La Jolla, USA(2)
The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and an increased risk of age-related disease. The researchers found that Alzheimer’s disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. Finally, the researchers show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD.
Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease
Jerome Mertens(1), Fred H. Gage(1), Joseph R. Herdy(2)
Added on: 12-16-2022
Basal ganglia organoids to study Tourette Syndrome
November 2022
Yale University, New Haven, USA
Tourette Syndrome (TS) is a neuropsychiatric disorder thought to involve a reduction of basal ganglia (BG) interneurons and malfunctioning of the BG circuitry. However, whether interneurons fail to develop or are lost postnatally remains unknown. To investigate the pathophysiology of early development in TS, induced pluripotent stem cell (iPSC)-derived BG organoids from TS patients and healthy controls were compared on multiple levels of measurement and analysis. BG organoids from TS individuals manifested differentiation and transcriptomic differences, revealing organoid mispatterning in TS. This study uncovers early neurodevelopmental underpinnings of TS neuropathological deficits using organoids as a model system.
Mispatterning and interneuron deficit in Tourette Syndrome basal ganglia organoids
Flora M. Vaccarino
Added on: 01-19-2023
COVID-19-related immune signatures and neurological sequelae
November 2022
University Hospital Basel, Basel, Switzerland
COVID-19 is associated with acute and long-term neurological dysfunction, but the pathophysiological mechanisms resulting in central nervous system involvement remain unclear.
To address this issue, a cross-sectional clinical study was performed, including clinical and imaging data and corresponding multidimensional characterization of immune mediators in the cerebrospinal fluid (CSF) and plasma of patients belonging to different Neuro-COVID severity classes.
40 COVID-19 patients, 25 healthy controls and 25 patients with neurological inflammation of other causes were included in the study and the findings obtained from clinical sample analysis were correlated with brain imaging.
The most prominent signs of severe Neuro-COVID are blood-brain barrier impairment, elevated microglia activation markers and a polyclonal B cell response targeting self-antigens and non-self-antigens. Specific CSF and plasma alterations were identified, which provide insights into the pathomechanism underlying COVID-19-related neurological sequelae. Moreover, several potentially actionable targets to prevent or intervene with the neurological consequences of SARS-CoV-2 infection were identified.
Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study
Gregor Hutter
Added on: 11-21-2022
Efficacy test of an antivirostatic drug on SARS-CoV-2 infected brain organoids
November 2022
University of California San Diego, La Jolla, USA
In addition to respiratory symptoms, patients with COVID-19 disease may also present with neurological symptoms. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, in this study iPSC-derived human brain organoids were infected. It was shown that SARS-CoV-2 can productively replicate and promote the death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, the authors found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. These results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms.
SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir
Alysson R. Muotri
Added on: 11-15-2022
In silico identification of multi-target ligands for neurodegenerative diseases drug development
November 2022
Bulgarian Academy of Sciences, Sofia, Bulgaria
The conventional treatment of neurodegenerative diseases (NDDs) is based on the “one molecule—one target” paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as “multi-target-directed ligands” (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. In this study, more than 650,000 compounds were screened by a series of in silico approaches to identify drug-like compounds with predicted activity simultaneously towards three important proteins in the NDDs symptomatic treatment. Four selected hits underwent subsequent refinement through in silico blood-brain barrier penetration estimation, safety evaluation, and molecular dynamics simulations, resulting in two hit compounds that constitute a rational basis for further development of multi-target active compounds against NDDs.
In silico identification of multi-target ligands as promising hit compounds for neurodegenerative diseases drug development
Nikolay T. Tzvetkov, Ivanka Tsakovska
Added on: 11-28-2022
Multielectrode arrays to study human motor neurons in vivo
November 2022
Chalmers University of Technology, Gothenburg, Sweden(1)
Imperial College London, London, United Kingdom(2)
Imperial College London, London, United Kingdom(2)
Within this study, a high-density intramuscular electrode for in vivo human recordings was developed along with a fully automatic methodology for the detection of the discharges of action potentials of up to 67 concurrently active motoneurons.
The thin-film electrode array contained 40 electrodes and the flexibility of the array allowed its insertion into the hole of a needle. Thus the intramuscular implantation of the electrodes could be performed with needles. Four intramuscular electrode arrays were tested in three healthy subjects. The volunteers were asked to contract the muscles with different intensities and signals of motor neurons were recorded and analyzed.
The system was shown to be able to analyze the human motor system in vivo.
Blind identification of the spinal cord output in humans with high-density electrode arrays implanted in muscles
Silvia Muceli(1), Dario Farina(2)
Added on: 03-13-2023
Rebooting the immune system in MS therapy
November 2022
University and University Hospital Zurich, Zurich, Switzerland
Autologous hematopoietic stem cell transplantation (aHSCT) is a highly effective treatment of multiple sclerosis (MS), as it depletes autoreactive cells and subsequently renews adaptive immune cells.
This study investigates the T cell depletion during aHSCT and the T cell renewal after aHSCT in MS. Therefore, the dynamics of new and surviving T cells was examined in 27 patients after aHSCT. Moreover, 12 healthy persons and 16 patients with untreated MS were included in the study. Lymphocytes of the participants were investigated by multidimensional flow cytometry, T cell receptor sequencing, specificity testing, and human leukocyte antigen (HLA) genotyping over a period of 2 years.
The data showed substantial survival of autoreactive CD4+ T cells early after transplantation but a complete renewal of the T cell repertoire later.
In addition, the authors performed a complete characterization of the renewed T cell population. The results will provide a valuable resource for understanding the mechanisms mediating the efficacy of aHSCT in patients with MS.
Dynamics of T cell repertoire renewal following autologous hematopoietic stem cell transplantation in multiple sclerosis
Roland Martin
Added on: 11-15-2022
T cell responses predict progression of amyotrophic lateral sclerosis
November 2022
Karolinska Institutet, Stockholm, Sweden
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, involving neuroinflammation and T-cell infiltration in the central nervous system. However, the contribution of T-cell responses to the pathology of the disease is not fully understood. Here the researchers show, by analysing blood and cerebrospinal fluid (CSF) samples of 89 newly diagnosed ALS patients, that T-cell phenotypes at the time of diagnosis are good predictors of disease outcome. Certain types of T-cells in blood and CSF are associated with poor survival, whereas other types of T-cells in the blood are associated with better survival. Besides survival, phenotypic profiling of T-cells could also predict disease progression rate. In summary, T-cell responses are associated with and likely contribute to disease progression in ALS, supporting the modulation of adaptive immunity as a viable therapeutic option.
T cell responses at diagnosis of amyotrophic lateral sclerosis predict disease progression
Fang Fang, John Andersson
Added on: 01-05-2023
3D-fabricated scaffolds for glioma research
October 2022
Delft University of Technology, Delft, Netherlands(1)
Erasmus MC Cancer Institute, Rotterdam, Netherlands(2)
Erasmus MC Cancer Institute, Rotterdam, Netherlands(2)
A major obstacle in glioma research is the lack of in vitro models that can retain the cellular features of glioma cells in vivo. To overcome this limitation, a 3D-engineered scaffold, fabricated by two-photon polymerization, is developed as a cell culture model system to study patient-derived glioma cells. Scanning electron microscopy, (live cell) confocal microscopy and immunohistochemistry are employed to assess the 3D model with respect to scaffold colonization, cellular morphology, and epidermal growth factor receptor localization. Both glioma patient-derived cells and established cell lines successfully colonize the scaffolds. Compared to conventional 2D cell cultures, the 3D-engineered scaffolds more closely resemble in vivo glioma cellular features and allow better monitoring of individual cells, cellular protrusions, and intracellular trafficking. Furthermore, less random cell motility and increased stability of cellular networks are observed for cells cultured on the scaffolds. The 3D-engineered glioma scaffolds, therefore, represent a promising tool for studying brain cancer mechanobiology as well as for drug screening studies.
3D-engineered scaffolds to study microtubes and localization of epidermal growth factor receptor in patient-derived glioma cells
Angelo Accardo(1), Pim J. French(2)
Added on: 12-14-2022
A brain injury model based on resected tissue
October 2022
Keele University, Staffordshire, United Kingdom
This study describes a protocol to use donor cerebellar tissue surgically resected from patients with Chiari malformation (which is a congenital abnormality characterized by downward displacement of cerebellar tissue into the spinal canal) to develop an in-vitro model of traumatic brain injury.
5 patient-derived tissue samples were used in this study and each tissue sample was processed into 35 to 48 tissue slices. Culture conditions were optimized, a protocol to introduce a traumatic injury in the model was developed and it was evaluated if it is feasible to implant a surgical-grade scaffold for regeneration into the injury site.
Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices and biomaterial placement was also feasible within the in-vitro lesions. Accordingly, this proof-of-concept study demonstrated that the model offers potential for preclinical testing in neural tissue engineering.
A benchtop brain injury model using resected donor tissue from patients with Chiari malformation
Divya M. Chari
Added on: 10-26-2022
Effect of adenosine A1 receptor mutation in Parkinson´s disease studied in human cells
October 2022
National Institutes of Health, Baltimore, USA(1)
Universitat Autònoma Barcelona, Barcelona, Spain(2)
University of Barcelona, L’Hospitalet de Llobregat, Spain(3)
Universitat Autònoma Barcelona, Barcelona, Spain(2)
University of Barcelona, L’Hospitalet de Llobregat, Spain(3)
An autosomal-recessive mutation within the adenosine A1 receptor (A1R) is associated with the development of early-onset Parkinson’s disease. In this study, the impact of this mutation on the structure and function of A1R and its heteromerization with the adenosine A2A receptor (A2AR) was investigated.
Human embryonic kidney (HEK) cells were transfected with A1R (wild type and mutated receptor), as well as with human A2AR. It was shown, that the mutation does not alter A1R expression, ligand binding, constitutive activity or coupling to transducer proteins. However, the mutation weakened the ability of A1R to heteromerize with A2AR, which led to the disappearance of the heteromerization-dependent negative modulation that A1R imposes on the activity of A2AR. Molecular dynamic simulations allowed the researchers to propose an indirect mechanism by which the mutation weakens the interface of the A1R-A2AR heteromer.
Therefore, it is demonstrated that the mutation is associated with dysfunction of adenosine receptor heteromerization, which can represent a novel target for the treatment of early-onset Parkinson’s disease.
The ADORA1 mutation linked to early-onset Parkinson’s disease alters adenosine A1-A2A receptor heteromer formation and function
Sergi Ferré(1), Leonardo Pardo(2), Francisco Ciruela(3)
Added on: 11-15-2022
Huntington’s disease modelled in patient-derived neurons
October 2022
Washington University School of Medicine, St. Louis, USA
Huntington’s disease (HD) is an inherited neurodegenerative disorder with adult-onset clinical symptoms, but the mechanism by which ageing drives the onset of neurodegeneration in patients with HD remains unclear. In this study striatal medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of patients with HD were examined to model the age-dependent onset of pathology. It could be found that pronounced neuronal death occurred selectively in reprogrammed MSNs from symptomatic patients with HD (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and control MSNs from age-matched healthy individuals. Age-associated alterations in chromatin accessibility between HD-MSNs and pre-HD-MSNs were observed and the microRNA miR-29b-3p was identified, the age-associated upregulation which promotes HD-MSN degeneration. Reducing miR-29b-3p or chemically promoting autophagy increased the resilience of HD-MSNs against neurodegeneration. The results demonstrate miRNA upregulation with ageing in HD as a detrimental process driving MSN degeneration and potential approaches for enhancing autophagy and resilience of HD-MSNs.
Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy
Andrew S. Yoo
Added on: 11-21-2022
Investigation of the pathogenesis of Alzheimer’s disease via a longitudinal study
October 2022
Karolinska Institute, Stockholm, Sweden(1)
University of Cincinnati, Cincinnati, USA(2)
University of Cincinnati, Cincinnati, USA(2)
The disease pathogenesis of Alzheimer´s disease is associated with plaques forming from the soluble peptide amyloid-β. However, it could arise from either of two ends of the process: the increase in insoluble amyloid plaques or the depletion of the soluble peptide, which has important functions.
In this retrospective longitudinal study the hypothesis was tested, that in individuals with amyloid plaques carrying certain Alzheimer's disease-causing mutations, higher levels of soluble amyloid-β reduce the risk of cognitive progression. The cognitive function of 108 patients was quantified over 3 years, and cerebrospinal fluid biomarkers including soluble amyloid- β were determined. Neuroimaging was used to quantify the burden of insoluble brain amyloid plaques.
The results demonstrate that higher levels of soluble amyloid- β levels predict a lower risk of cognitive progression. Thus this study revealed that brain toxicity in Alzheimer's disease may be predominantly mediated by a reduction of the soluble protein pool, rather than its accrual into amyloid plaques.
High soluble amyloid-β42 predicts normal cognition in amyloid-positive individuals with Alzheimer’s disease-causing mutations
Andrea Sturchio(1), Alberto J. Espay(2)
Added on: 10-31-2022
iPSC-derived neurons from PTSD patients
October 2022
Icahn School of Medicine at Mount Sinai, New York, USA(1)
The New York Stem Cell Foundation Research Institute, New York, USA(2)
The New York Stem Cell Foundation Research Institute, New York, USA(2)
Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, the researchers compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD and controls. In neurons only, the authors observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.
Modeling gene x environment interactions in PTSD using human neurons reveals diagnosis-specific glucocorticoid-induced gene expression
Kristen J. Brennand(1), Rachel Yehuda(1), Daniel Paull(2)
Added on: 04-25-2023
Low-cost transdermal biomarker sensing device
October 2022
ISEP School of Engineering, Polytechnic Institute, Porto, Portugal(1)
Swansea University, Swansea, United Kingdom(2)
Swansea University, Swansea, United Kingdom(2)
The skin interstitial fluid (ISF) contains biomarkers that complement other biofluids such as blood, sweat, saliva, and urine. It can be sampled in a minimally invasive manner and used either for point-of-care testing or real-time, continuous monitoring of analytes, the latter using microneedle arrays. In this study, the researchers describe combining microneedle technology with molecularly imprinted polymers to demonstrate the potential of transdermal electrochemical sensing. The molecularly imprinted polymer employed here is easy to produce; it can be thought of as a plastic antibody, detecting proinflammatory cytokine IL-6 that is present in many pathologic conditions of neurodegenerative diseases such as Alzheimer´s or Parkinson´s disease. Its synthesis is scalable, and the resulting sensor has a short measurement time (6 min), with high accuracy and a low limit of detection. The ability to mass-produce microneedle arrays and plastic antibodies will allow for low-cost transdermal sensing devices. The device could be used for routine point-of-care, and bloodless measurements in simpler settings, worldwide.
Molecular imprinted polymers on microneedle arrays for point of care transdermal sampling and sensing of inflammatory biomarkers
Felismina Teixeira Coelho Moreira(1), Sanjiv Sharma(2)
Added on: 01-19-2023
Microstructural alterations in Alzheimer´s disease
October 2022
Karolinska Institute, Stockholm, Sweden
The goal of this study was to investigate neurodegeneration of the human cholinergic system using diffusion-weighted magnetic resonance imaging (MRI) across different stages of Alzheimer’s disease.
Therefore microstructural alterations of two major cholinergic pathways were investigated in individuals along the Alzheimer’s disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. 402 participants, including patients with different stages of Alzheimer’s disease and healthy controls, were included in the study. In addition to MRI participants performed neuropsychological tests and cerebrospinal fluid biomarkers were analyzed.
Cholinergic white matter pathways were modelled with an enhanced diffusion neuroimaging pipeline and compared between the different stages of Alzheimer’s disease and in relation to cognitive performance.
Cholinergic white matter pathways along the Alzheimer’s disease continuum
Daniel Ferreira
Added on: 03-20-2023
Neurotoxicological hazard assessment with a human cell-based battery
October 2022
IUF - Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany(1)
University of Konstanz, Konstanz, Germany(2)
University of Konstanz, Konstanz, Germany(2)
Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. Therefore test methods with high throughput and human relevance are urgently needed. Here the feasibility of DNT hazard assessment based on new approach methods (NAMs) was explored. An in vitro battery (IVB) was assembled from ten individual NAMs to probe the effects of chemicals on various fundamental neurodevelopmental processes. All assays used human neural cells at different developmental stages. This allowed the assessment of disturbances of (i) proliferation of neural progenitor cells (NPC); (ii) migration of neural crest cells, radial glia cells, neurons and oligodendrocytes; (iii) differentiation of NPC into neurons and oligodendrocytes; and (iv) neurite outgrowth of peripheral and central neurons. In parallel, cytotoxicity measurements were obtained. The feasibility of concentration-dependent screening and of reliable biostatistical processing of the complex multi-dimensional data was explored with a set of 120 test compounds, containing subsets of pre-defined positive and negative DNT compounds. The battery provided alerts (hit or borderline) for 24 of 28 known toxicants (82% sensitivity), and for none of the 17 negative controls. Based on the results from this screen project, strategies were developed on how IVB data may be used in the context of risk assessment scenarios employing integrated approaches for testing and assessment (IATA).
Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals
Ellen Fritsche(1), Jonathan Blum(2), Marcel Leist(2)
Added on: 12-02-2022
Monochromatic light modifies neural connections
2022
Universitat Politècnica de Catalunya, Terrassa, Spain
Growing research indicates that light exposure can positively impact health-related problems such as spring asthenia, circadian rhythm disruption, and even bipolar disorders and Alzheimer’s. However, the extent and location of changes in brain areas caused by exposure to monochromatic light remain largely unknown. In this pilot study with seven participants, functional magnetic resonance is used to show light-dependent functional connectivity patterns on brain networks. The researchers demonstrated that 1 min of blue, green, or red light exposure modifies the functional connectivity of a broad range of visual and non-visual brain regions. Results can be relevant for future research on the impact of light stimulation on brain function and in various health disciplines.
Functional connectivity of brain networks with three monochromatic wavelengths: a pilot study using resting-state functional magnetic resonance imaging
Marc Argilés
Added on: 01-19-2023
Novel synthetic clot analogs for in vitro stroke modelling
2022
University Medical Center Hamburg-Eppendorf, Hamburg, Germany
The increased demand for the training of mechanical thrombectomy in ischemic stroke and the development of new recanalization devices urges the creation of new simulation models both for training and device assessment. Clots properties have been shown to play a role in procedural planning and thrombectomy device effectiveness. In this study, the researchers analysed the characteristics and applicability of completely synthetic, animal-free clots in the setting of an in vitro model of mechanical thrombectomy for training and device assessment. Synthetic clots based on agarose and silicone were evaluated in an in-vitro neurointervention simulation of mechanical thrombectomy with clot extraction devices. Calcified clots of mixed nature were simulated with the addition of 3D-printed structures. Both agarose-based and silicone-based clots demonstrated relevant flow arrest and good integration with the clot extraction device. Silicone-based clots scored higher on adherence to the vessel wall and elasticity. Selected synthetic clots can successfully be implemented in an in-vitro training environment of mechanical thrombectomy. The clots' different properties might serve to mimic fibrin-rich and red blood cell-rich human thrombi.
Novel synthetic clot analogs for in-vitro stroke modelling
Helena Guerreiro
Added on: 10-25-2022
Spatio-temporal control of hypoxia in in-vitro models
2022
University of Cambridge, Cambridge, United Kingdom
In this study, the principle of electrochemical Localised Oxygen Scavenging (eLOS) was studied to apply acute hypoxia in in-vitro cell models. Therefore, the oxygen gradient was investigated next to a polarized electrode, and a design was developed to induce the spatiotemporal hypoxia via electrochemical oxygen scavenging.
The system was evaluated using human neural progenitor cells, to show the spatiotemporal gradient of the hypoxic response. The platform was further integrated into a microchannel device to study a human cortical infarct model with pluripotent stem cell (PSC)-derived human neurons. It was demonstrated that eLOS can improve control of hypoxia in timescales of acute and chronic hypoxia.
The versatile system can be further adapted for studying tumor microenvironment, myocardial infarction and other ischaemic systems in-vitro.
Electrochemically induced in vitro focal hypoxia in human neurons
Elizabeth A. H. Hall
Added on: 10-31-2022
Human organ chip for space biology studies
2022
National Aeronautics and Space Administration (NASA) Ames Research Center, Moffett Field, USA
Central nervous system (CNS) damage by galactic cosmic ray radiation is a major health risk for astronauts. Astrocytes are major cellular regulators of blood-brain barrier permeability that also modulate neuroinflammation and neuronal health. However, astrocyte roles in regulating CNS and blood-brain barrier responses to space radiation remain little understood. In this work, a high-throughput organ-on-a-chip system seeded with human iPSC-astrocytes and/or brain endothelial cells was used to evaluate blood-brain barrier impairments and astrocyte functions 1-7 days after exposure to 600 MeV/n 56Fe particles and simplified simulated galactic cosmic rays. It was shown that simulated deep space radiation causes vascular permeability, oxidative stress, inflammation and delayed astrocyte activation in a pattern resembling CNS responses to brain injury. Furthermore, the results indicate that astrocytes have a dual role in regulating radiation responses: they exacerbate blood-brain barrier permeability acutely after irradiation, followed by switching to a more protective phenotype by reducing oxidative stress and pro-inflammatory cytokine and chemokine secretion during the subacute stage.
Overall, the human CNS model used in this study suggests astrocyte regulatory mechanisms as targets for countermeasures to mitigate human BBB impairments during deep space exploration. Furthermore, this method could be helpful for future space biology studies.
Astrocytes regulate vascular endothelial responses to simulated deep space radiation in a human organ-on-a-chip model
Egle Cekanaviciute
Added on: 11-16-2022
Optimization of fMRI-based mapping
2022
University Hospital Frankfurt, Frankfurt, Germany
The definition of regions of interest in fMRI is often complicated due to the considerable interindividual variability of the cerebral cortex. Therefore, the aim of this study was to optimize fMRI-based mapping.
Different approaches to localize regions of interest were investigated and compared for 50 participants. These included cortex-based alignment, volume-based alignment and a surface-based analysis. During the functional imaging a series of flickering black-and white-colored checkerboard stimuli were shown and participants had to press a button when the central squares of the checkerboard changed their color to yellow.
Cortex-based alignment was shown to lead to best results. Since localization of regions of interest is crucial for investigating contributions of the visual system to cognitive processes, the results could have implications for the study of visual cognition in basic and translational neuroscience research. This could be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.
Improved correspondence of fMRI visual field localizer data after cortex‑based macroanatomical alignment
Robert A. Bittner
Added on: 04-24-2023
Photo-thermal therapy in a 3D bioprinted glioblastoma model
2022
Sapienza University of Rome, Latina, Italy
Photo-thermal therapy (PTT) is a minimally invasive cancer treatment that relies on the capability of photosensitizing agents to generate highly localized thermal heating for the selective thermal ablation of tumors. This study reports on a powerful combination of 3D bioprinting (3DB) and PTT applications. To this end, the researchers realize a 3DB construct consisting of glioblastoma U87-MG cells in a 3D geometry, incorporating biomimetic keratin-coated gold nanoparticles (Ker-AuNPs) as a photo-thermal agent. The resulting plasmonic 3DB structures exhibit a homogeneous cell distribution throughout the entire volume while promoting the localization of Ker-AuNPs within the cells. Laser-assisted PTT experiments demonstrate the extraordinary ability of Ker-AuNPs to generate heating, producing the highest temperature rise of about 16 °C in less than 2 min.
Biomimetic keratin-coated gold nanoparticles for photo-thermal therapy in a 3D bioprinted glioblastoma tumor model
Luciano De Sio
Added on: 10-25-2022
Shell microelectrode arrays for brain organoids
2022
Johns Hopkins University, Baltimore, USA
Brain organoids are important models for mimicking some three-dimensional (3D) cytoarchitectural and functional aspects of the brain. Multielectrode arrays (MEAs) that enable the recording and stimulation of activity from electrogenic cells offer notable potential for interrogating brain organoids. However, conventional MEAs, initially designed for monolayer cultures, offer a limited recording contact area restricted to the bottom of the 3D organoids. Inspired by the shape of electroencephalography caps, in this study miniaturized wafer-integrated MEA caps for organoids were developed. The optically transparent shells are composed of self-folding polymer leaflets with conductive polymer–coated metal electrodes. Tunable folding of the minicaps’ polymer leaflets guided by mechanics simulations enables versatile recording from organoids of different sizes, and the feasibility of electrophysiology recording from 400- to 600-μm-sized organoidswas validated for up to 4 weeks and in response to glutamate stimulation. These studies suggest that 3D shell MEAs offer great potential for high signal-to-noise ratio and 3D spatiotemporal brain organoid recording.
Shell microelectrode arrays (MEAs) for brain organoids
David H. Gracias
Added on: 10-14-2021
Brain model to study chemical-induced dopaminergic neuronal toxicity
2022
Johns Hopkins University, Baltimore, USA
In the context of Parkinson's disease (PD), the sensitivity of dopaminergic neurons in the substantia nigra pars compacta to oxidative stress is considered a key factor of PD pathogenesis. Here the effect of different oxidative stress-inducing compounds (6-OHDA, MPTP or MPP+) on the population of dopaminergic neurons was studied in an iPSC-derived human brain 3D model (aka BrainSpheres). Treatment with 6-OHDA, MPTP or MPP+ at 4 weeks of differentiation disrupted the dopaminergic neuronal phenotype in BrainSpheres. 6-OHDA increased the production of reactive oxygen species and decreased mitochondrial function most efficiently. It further induced the greatest changes in gene expression and metabolites related to oxidative stress and mitochondrial dysfunction. Co-culturing BrainSpheres with an endothelial barrier using a transwell system allowed the assessment of differential penetration capacities of the tested compounds and the damage they caused in the dopaminergic neurons within the BrainSpheres. In conclusion, treatment with compounds known to induce PD-like phenotypes in vivo caused molecular deficits and loss of dopaminergic neurons in the BrainSphere model. This approach, therefore, recapitulates neurodegenerative processes in PD and could be relevant as a tool for drug discovery.
Human iPSC 3D brain model as a tool to study chemical-induced dopaminergic neuronal toxicity
David Pamies
Added on: 05-12-2022
Brain-on-chip to model neuroinflammation in humans
Company 2022
Emulate Inc., Boston, USA
Here, a human organotypic microphysiological system (MPS) was presented that includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains blood-brain-barrier (BBB) permeability at in vivo relevant levels. This human Brain-Chip is engineered to recapitulate critical aspects of the complex interactions that mediate neuroinflammation and demonstrates significant improvements in clinical mimicry compared to previously reported similar MPS. In comparison to Transwell culture, the transcriptomic profiling of the Brain-Chip displayed significantly advanced similarity to the human adult cortex and enrichment in key neurobiological pathways. Exposure to TNF-α recreated the anticipated inflammatory environment shown by glia activation, increased release of proinflammatory cytokines, and compromised barrier permeability. In summary, the development of a robust brain MPS for the mechanistic understanding of cell-cell interactions and BBB function during neuroinflammation was reported.
A microengineered brain-chip to model neuroinflammation in humans
Katia Karalis, Iosif Pediaditakis
Added on: 11-14-2022
Immune cell-tumor interaction-on-a-chip
2022
National Research Council, Genoa, Italy
In this study, an organ-on-chip-based approach for recapitulating the immune cell migration and infiltration within a 3D tumor matrix is presented. Human neuroblastoma cells were embedded in a hydrogel matrix and cultured in a compartment physically separated from the fluid flow compartment of the microfluidic device through a porous permeable membrane. Natural killer (NK) cells were isolated from blood of healthy volunteers.
The NK cells were able to migrate into the tumor compartment, and it was demonstrated that their migration is specifically mediated by soluble factors released by the tumor cells. Moreover, the NK cells retained their ability to interact with the tumor cells, and to display a cytotoxic effect resulting in tumor cell apoptosis.
The model represents a promising approach for the screening of the anti-tumor activity of both, drug-based and cell-based therapies. Moreover, it allows the investigation of tumor-immune cell interactions.
A multi-organ-on-chip to recapitulate the infiltration and the cytotoxic activity of circulating NK cells in 3D matrix-based tumor model
Silvia Scaglione
Added on: 10-19-2023
3D tissue models for screening of neuroprotective compounds in Alzheimer's
2022
Tufts University, Medford, USA
Here, the researchers describe the use of 2D and 3D tissue culture models of herpesvirus-induced Alzheimer's Disease (AD), which recapitulate hallmark disease features of plaque formation, gliosis, neuroinflammation, and impaired neuronal signalling. They used these models to screen a panel of 21 medications, supplements, and nutraceuticals with purported neuroprotective benefits. This screen identified green tea catechins and resveratrol as having strong anti-plaque properties, functional neuroprotective benefits, and minimal neurotoxicity, providing support for their further investigation as AD preventives and therapies. Two other candidates, citicoline and metformin, reduced plaque formation and were minimally toxic, but did not protect against virus-induced impairments in neuronal signalling. This study establishes a simple platform for rapidly screening and characterizing AD compounds of interest in 2D and 3D human cortical tissue models representing physiologically relevant disease features.
Screening neuroprotective compounds in herpes-induced Alzheimer's disease cell and 3D tissue models
David L. Kaplan
Added on: 01-05-2023
A potential biomarker for Sudden Infant Death Syndrome
2022
The Children's Hospital at Westmead, Westmead, Australia
Autonomic dysfunction has been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Butyrylcholinesterase (BChE) is an enzyme of the cholinergic system, a major branch of the autonomic system, and may provide a measure of autonomic (dys)function. This study was undertaken to evaluate BChE activity in infants and young children who had died from Sudden Infant Death or Sudden Unexpected Death. The researchers measured BChE specific activity (BChEsa) and total protein in the eluate of dried blood spots taken at birth as part of the newborn screening program. BChEsa, measured in dried blood spots taken 2-3 days after birth, was lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. The researchers conclude that a previously unidentified cholinergic deficit, identifiable by abnormal BChEsa, is present at birth in SIDS babies and represents a measurable, specific vulnerability prior to their death. This finding represents the possibility for the identification of infants at risk for SIDS prior to death and opens new avenues for future research into specific interventions.
Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome
Carmel Therese Harrington
Added on: 06-09-2022
Glioblastoma organoids for selection of personalized therapies
2022
Luxembourg Institute of Health, Dudelange, Luxembourg(1)
Mannheim Center for Translational Neurosciences, Mannheim, Germany(2)
Mannheim Center for Translational Neurosciences, Mannheim, Germany(2)
This study describes the establishment of a patient-derived glioblastoma organoid (PD-GBO) based functional profiling platform and the results of its application to four patient tumors. It was shown that the PD-GBO model system preserves key features of individual patient glioblastomas. As proof of concept, a panel of 41 FDA-approved drugs was tested and used to identify potential treatment options for three out of four patients within a turnaround from tumor resection to discovery of treatment options of 13, 14, and 15 days, respectively. These results demonstrate that PD-GBOs can be used for effective personalized treatment discovery in a clinically relevant time period. Furthermore, these results warrant the use of PD-GBO platforms for the preclinical identification of new drugs against defined morphological glioblastoma features.
Patient-derived tumor organoids for guidance of personalized drug therapies in recurrent glioblastoma
Yong-Jun Kwon(1), Miriam Ratliff(2)
Added on: 10-14-2022
In-vitro model of peripheral neuropathies
2022
University of Konstanz, Konstanz, Germany
In vitro models of the human peripheral nervous system (PNS) are required to study chemotherapy-induced peripheral neuropathy (CIPN) and other impairments of the PNS. In this study, induced pluripotent stem cells (iPSCs) were harnessed to generate peripheral sensory neurons enriched in nociceptors and a corresponding protocol was established.
After extensive phenotypic profiling, Ca2+-imaging was chosen as a quantitative endpoint for the assessment of pain-receptor signalling. A case study with the chemotherapeutic drug oxaliplatin at non-cytotoxic concentrations was performed to demonstrate the relevance of the novel PNS model. Neuronal hypersensitivity to otherwise non-activating mechanical stimulation was found that could be blocked by modulators of voltage-gated sodium channels.
These findings indicate that the model is suitable for pharmacological and toxicological studies related to peripheral neuropathies.
Generation of human nociceptor-enriched sensory neurons for the study of pain-related dysfunctions
Marcel Leist
Added on: 09-01-2022
Neurotoxicity in the human neural progenitor cell test (hNPT) revealed by RNA-seq
2022
National Institute for Public Health and Environment, Bilthoven, Netherlands
This study presents the human neural progenitor test (hNPT), a 10-day protocol in which neural progenitor cells differentiate into a neuron-astrocyte co-culture. The aim of the investigation was to characterise differentiation over time and to find neurodevelopmental processes sensitive to compound exposure using transcriptomics. Exposure to compounds with known or suspected developmental neurotoxicity regulated unique combinations of gene ontology (GO)-terms relating to neural progenitor proliferation, neuronal and glial differentiation, axon development, synaptogenesis, synaptic transmission, and apoptosis. Investigation of the GO-terms revealed common genes that were responsive across compounds and might be used as biomarkers for developmental neurotoxicity, while other GO-terms may articulate compound-specific effects that may be relevant for revealing mechanisms of toxicity. Due to its detailed molecular readout based on gene expression analysis, hNPT might have added value for neurodevelopmental toxicity testing in vitro.
Neuronal differentiation pathways and compound-induced developmental neurotoxicity in the human neural progenitor cell test (hNPT) revealed by RNA-seq
Victoria C. de Leeuw
Added on: 06-22-2022
Target protein for diabetes drug linked to reduced the risk of Alzheimer’s disease
2022
Karolinska Institutet, Stockholm, Sweden
A gene association study design was applied to examine the association between genetic variation in the targets of four anti-diabetic drug classes and Alzheimer´s disease AD risk. The researchers analysed data from over 300,000 participants in the UK Biobank register, as well as from more than 24,000 clinically diagnosed AD cases and 55,000 controls. The results show that genetic variation in sulfonylurea targets was associated with a lower risk of AD, and future studies are warranted to clarify the underlying mechanistic pathways between sulfonylureas and AD.
Genetic variation in targets of anti-diabetic drugs and Alzheimer disease risk: a Mendelian randomization study
Sara Hägg
Added on: 09-08-2022
3D bioprinted model of neuroblastoma recapitulates tumor-endothelial cell interactions
2022
Emory University School of Medicine, Atlanta, USA(1)
Emory University School of Medicine and Georgia Institute of Technology, Atlanta, USA(2)
Emory University School of Medicine and Georgia Institute of Technology, Atlanta, USA(2)
Neuroblastoma (NB) is the most common extracranial tumor in children and results in significant morbidity and mortality. A deeper understanding of the tumor microenvironment (TME) of NB remains an active area of research but lacks reliable and biomimetic models. In this study, a 3D bioprinting approach is used in combination with NB spheroids to create an in vitro vascular model of NB to study tumor function within an endothelialized microenvironment. A gelatin methacryloyl (gelMA) bioink is used to create multichannel cubic tumor analogues with high print fidelity and mechanical tunability. Human NB spheroids and umbilical vein endothelial cells (HUVECs) are integrated into the biologically engineered gelMA and co-cultured under static and dynamic conditions, showing high levels of survival and growth. Quantification of NB-EC integration and tumor cell migration suggests increased aggressive behaviour of NB when cocultured with HUVECs in bioengineered endothelialized models. This model also allows the assessment of metabolic, cytokine, and gene expression profiles of NB spheroids under different TME conditions. These results create a high-throughput research platform to study TME-mediated cellular-molecular mechanisms of tumor growth, aggression, and response to therapy.
A 3D bioprinted in vitro model of neuroblastoma recapitulates dynamic tumor-endothelial cell interactions contributing to solid tumor aggressive behavior
Kelly C. Goldsmith(1), Vahid Serpooshan(2)
Added on: 10-28-2022
3D bioprinting as a tool to study amyotrophic lateral sclerosis
2022
IRCCS Mondino Foundation, Pavia, Italy
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease (NDD) that affects motor neurons, causing weakness, muscle atrophy and spasticity. Unfortunately, there are only symptomatic treatments available. The aim of this work was to demonstrate the robustness of 3D cultures for the differentiation of stem cells for the study of ALS. The authors reprogrammed peripheral blood mononuclear cells (PBMCs) from healthy individuals and patients with ALS in iPSCs and differentiated them into neural stem cells (NSCs) in 2D. NSCs were printed in 3D hydrogel-based constructs and subsequently differentiated first in motor neuron progenitors and finally in motor neurons. Every step of differentiation was tested for cell viability and characterized by confocal microscopy and RT-qPCR. Finally, the electrophysiological characteristics of included NSC34 were tested. It was found that NSCs maintained good viability during the 3D differentiation. The results suggest that the hydrogel does not interfere with the correct differentiation process or with the electrophysiological features of the included cells. Such evidence confirmed that 3D bioprinting can be considered a good model for the study of ALS pathogenesis.
Patients’ stem cells differentiation in a 3D environment as a promising experimental tool for the study of amyotrophic lateral sclerosis
Orietta Pansarasa
Added on: 02-06-2023
Brain organoids to identify neural abnormalities and test gene therapy tools
2022
University of California San Diego, La Jolla, USA(1)
University of Campinas, Campinas, Brazil(2)
University of Campinas, Campinas, Brazil(2)
Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, the researchers derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome, an autism spectrum disorder, carrying clinically relevant mutations in TCF4. They show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons and identify a potentially clinically relevant mechanism. Moreover, they show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signalling. This work delineates pathological mechanisms in neural cells harbouring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.
Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Alysson R. Muotri(1), Fabio Papes(2)
Added on: 06-09-2022
Genetic study identifies therapeutic targets for migraines
2022
Queensland University of Technology (QUT), Brisbane, Australia
Migraine is a common complex disorder with a significant polygenic single-nucleotide polymorphism (SNP) heritability. Here, the researchers utilise genome-wide association study (GWAS) summary statistics to study pleiotropy between blood proteins and migraine under the polygenic model. They collected 4625 publicly available GWAS summary statistics for blood proteins and explored the extent of pleiotropy between migraine and the 325 blood proteins. Pleiotropy analyses link 58 blood proteins to migraine risk at genome-wide, gene and/or single-nucleotide polymorphism levels—suggesting shared genetic influences or causal relationships. The study suggests that Wnt activators that restore Wnt/β-catenin signalling in the brain could represent therapeutic tools against migraine.
Genetic analyses identify pleiotropy and causality for blood proteins and highlight Wnt/β-catenin signalling in migraine
Dale R. Nyholt, Hamzeh M. Tanha
Added on: 11-25-2022
Maternal autoantibody profiles as biomarkers for autism
2022
University of California, Davis, USA
Maternal autoantibody-related autism spectrum disorder (MAR ASD) is a subtype of autism in which pathogenic maternal autoantibodies (IgG) cross the placenta, access the developing brain, and cause neurodevelopmental alterations and behaviours associated with autism in the exposed offspring. The aim of this study was to validate previously identified MAR ASD patterns and their accuracy in predicting ASD risk in a prospective cohort employing maternal samples collected prior to parturition. The researchers used prenatal plasma from mothers of autistic children with or without co-occurring intellectual disability, intellectual disability without autism and general population controls. They found reactivity to one or more of nine previously identified MAR ASD patterns in 10% of the ASD group, demonstrating that the MAR ASD patterns could be used to assess ASD risk prior to symptom onset. Prenatal screening for these MAR patterns may lead to earlier identification of ASD and facilitate access to the appropriate early intervention services based on each child’s needs.
Maternal autoantibody profiles as biomarkers for ASD and ASD with co-occurring intellectual disability
Judy Van de Water
Added on: 11-28-2022
Non-invasive investigation of the human visual cortex
2022
Ernst Strüngmann Institute (ESI) for Neuroscience in Cooperation with Max Planck Society, Frankfurt, Germany
Strong gamma-band oscillations in the early visual cortex (the part of the cerebral cortex in which visual stimuli are processed) can be induced by homogeneous colour surfaces and particularly strong gamma oscillations have been reported for red stimuli. The aim of this study was to investigate, whether this strong response to red colour is based on the colour itself or on other factors.
Therefore, magnetoencephalography (MEG) was recorded for 30 human participants while presenting them with uniform, circular colour disks.
With colours that had identical luminance and identical colour contrast, it could not be confirmed that red stimuli induce stronger gamma responses compared to stimuli of other colours. Moreover, it was demonstrated that colour-induced gamma-band responses can be studied non-invasively in humans.
Human visual gamma for color stimuli
Pascal Fries, Benjamin J Stauch
Added on: 01-23-2023
Retinal cell map for retinal diseases therapies
2022
National Eye Institute, Bethesda, USA
Retinal degenerative diseases affect specific regions of the retinal pigment epithelium (RPE), suggesting the presence of functionally different RPE subpopulations. To identify these subpopulations in human eyes, the researchers generated the first complete morphometric map of the RPE at single-cell resolution using artificial intelligence-based software. They identified five concentric RPE subpopulations, including a ring of RPE cells with a cell area similar to the macula in the periphery of the eye. Moreover, they found that specific RPE subpopulations are differentially susceptible to monogenic and polygenic retinal diseases. The results obtained here will allow the study of molecular and functional RPE differences responsible for regional retinal diseases and will help develop precise cell and gene therapies for specific degenerative eye diseases.
Single-cell-resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity
Kapil Bharti
Added on: 11-25-2022
Ultra-powerful brain scanners in Parkinson’s disease treatmen choice
2022
University of Cambridge, Cambridge, United Kingdom(1)
University of Sydney, Sydney, Australia(2)
University of Sydney, Sydney, Australia(2)
To understand the causes of cognitive symptoms of Parkinson’s disease and progressive supranuclear palsy (PSP), the researchers used a new ultra-high strength ‘7T’ magnetic resonance images (MRI) scanner to measure changes in the brains of people with Parkinson’s disease, PSP, or in good health. 7T refers to the strength of the magnetic field; most MRI scanners tend to be 3T or below. While most MRI scanners can show structures at the level of detail of a grain of rice, 7T scanners, which have ultra-strong magnetic fields, can provide resolution at the size of a grain of sand. The scanners allowed the team to examine the locus coeruleus, a noradrenaline-producing brain region, of their subjects and confirm that the greater the level of damage to this region, the more severe their symptoms of apathy and the worse they performed at cognitive tests. The findings offer the hope of new treatments for these symptoms, as the ultra-powerful 7T scanner may help researchers and clinicians to identify the patients who will probably benefit the most from noradrenaline boosting drugs.
Locus coeruleus integrity from 7 T MRI relates to apathy and cognition in Parkinsonian disorders
Rong Ye(1), Claire O'Callaghan(2)
Added on: 06-23-2022
Bioprinted, vascularized neuroblastoma tumor environment model
2022
Medical University Innsbruck, Innsbruck, Austria
In this work, 3D bioprinting and fluidic chip technology were combined to generate a complex vascularized tumor-on-a-chip model. A perfused and micro-vascularized tumor environment model that is directly bioprinted into custom-manufactured fluidic chips was developed. In this model, a hydrogel matrix containing multiple cell types mimics the tumor microenvironment that promotes spontaneous micro-vessel formation by embedded endothelial cells. Bioprinted channels were coated with endothelial cells post printing to form a dense vessel-tissue barrier. Patient-derived neuroblastoma spheroids were added to the matrix during the printing process and grown for more than two weeks. It was demonstrated that micro-vessels are attracted by and grow into the tumor spheroids and that neuroblastoma cells invade the tumor environment as soon as the spheroids disrupt.
The bioprinted, micro-vascularized neuroblastoma tumor environment model thus represents a platform suitable for studying tumor angiogenesis and metastasis as well as for performing drug validation studies.
3D bioprinted, vascularized neuroblastoma tumor environment in fluidic chip devices for precision medicine drug testing
Michael J Ausserlechner, Judith Hagenbuchner
Added on: 09-01-2022
Reasons for autism investigated in minibrains
2022
Institute of Science and Technology (IST) Austria, Klosterneuburg, Austria(1)
IRCCS, Milan, Italy(2)
IRCCS, Milan, Italy(2)
Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a common cause of autism spectrum disorders (ASD). While the phenotypic spectrum often includes macrocephaly, suggestive of cortical abnormalities, it is unclear how CHD8 haploinsufficiency affects neurodevelopment. Examination of human cerebral organoids has revealed that CHD8 haploinsufficiency disrupts neurodevelopmental pathways with an accelerated and delayed formation of inhibitory and excitatory neurons, respectively, resulting in symmetrically opposite expansions of their proportions at 60 and 120 days. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patient macrocephaly. An isogenic design of patient-specific mutations and mosaic organoids defined genotype-phenotype relationships and revealed their cell-autonomous nature. The results define cell type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell type-specific effects of CHD8 mutations, the study uncovers reproducible developmental changes that can be used to model neurodegenerative diseases.
CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories
Gaia Novarino(1), Giuseppe Testa(2)
Added on: 04-20-2022
Human brain organoid to study JC virus infection
2022
Johns Hopkins University, Baltimore, USA
Progressive multifocal leukoencephalopathy (PML) is a common neurological complication in immunocompromised patients. PML is caused by JC virus (JCV), a neurotropic DNA polyomavirus that infects oligodendrocytes and astrocytes, causing inflammation and demyelination leading to neurologic dysfunction. The pathogenesis of PML is poorly understood to date, except that the virus infects only human cells.
Here, using human induced pluripotent stem cells (iPSCs), organotypic models were generated with neurons, astrocytes, and oligodendrocytes that mimic aspects of the human brain environment. These brain organoids were then infected with JCV strain MAD4 or CSF from a patient with PML.
At 1, 2, and 3 weeks after exposure, the organoids were examined for signs of infection by qPCR, immunofluorescence, and electron microscopy. The researchers detected JCV infection of oligodendrocytes, astrocytes, and media of both JCV-MAD4 strain-exposed and PML-liquor-exposed brain organoids. In contrast, no evidence of neuronal infection was detected. In conclusion, the brain organoid model of JCV infection represents a human model suitable for studying the mechanisms of JCV infection and the pathogenesis of PML and may facilitate the exploration of therapeutic approaches.
A human-derived 3D brain organoid model to study JC virus infection
Carlos A. Pardo
Added on: 04-14-2022
In-vitro cerebral tissues mimic circuit disturbances in 3D
2022
Eindhoven University of Technology, Eindhoven, Netherlands
In-vitro modelling of brain network disorders such as epilepsy remains a major challenge. A critical step is to develop an experimental approach that enables recapitulation of in-vivo-like three-dimensional functional complexity while allowing local modulation of the neuronal networks. Here, multiregional cerebral tissues with intact 3D neuronal networks and functional interconnectivity characteristics of brain networks were engineered by promoting matrix-supported active cell reaggregation. Furthermore, using a multi-chambered tissue-culture chip, it was shown that the separated but interconnected cerebral tissues can mimic neuropathological signatures such as the propagation of epileptiform discharges.
In-vitro engineered human cerebral tissues mimic pathological circuit disturbances in 3D
Nicholas A. Kurniawan, Aref Saberi
Added on: 01-27-2023
In-vitro screening for drug-induced neuropathy
2022
University of Konstanz, Konstanz, Germany
In this study, the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors is explored. Therefore, human sensory neurons were established from induced pluripotent stem cells and used to assess proteasome inhibitor-induced early alterations in signalling and morphology. Purinergic signalling was exploited as a sensitive endpoint affected by proteasome inhibitors. Moreover, the microtubule arrangement was studied as an indicator of initial morphological stress responses. A panel of five proteasome inhibitors was used to identify readouts of cell changes occurring well before signs of general cytotoxicity. P2X3 signalling proved useful as an endpoint to assess potential neurotoxicants. The presented model may be used for the profiling of new proteasome inhibitors in regard to their side effects (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity.
Specific attenuation of purinergic signaling during bortezomib-induced peripheral neuropathy in vitro
Marcel Leist
Added on: 05-31-2022
Machine learning models for early-stage Alzheimer's prediction
2022
Sathyabama Institute of Science and Technology, Chennai, India
In its early stages, Alzheimer's disease (AD) is hard to predict. A treatment given at an early stage of AD is more effective, and it causes fewer minor damage than a treatment done at a later stage. In this study, several computational techniques have been employed to identify the best parameters for Alzheimer's disease prediction. Predictions of Alzheimer's disease are based on MRI images from 150 patients from the Open Access Series of Imaging Studies (OASIS) database. Machine learning techniques were applied to Alzheimer's disease datasets to bring a new dimension to predict the disease at an early stage. The proposed classification scheme can be used by clinicians to make diagnoses of these diseases. The proposed work shows better results, with the best validation average accuracy of 83% on the test data of AD. This test accuracy score is significantly higher in comparison with existing works.
Early-stage Alzheimer's disease prediction using machine learning models
C. Kavitha
Added on: 09-14-2023
Mapping shows how the brain shrinks in Parkinson's disease
2022
Research Centre Jülich, Juelich, Germany
The neuropathological features of idiopathic Parkinson's disease (PD) are the degeneration of dopaminergic neurons in the striatum and the spread of aggregates of misfolded α-synuclein in the brain according to a specific pattern. However, the relationship between this pattern and motor and cognitive symptoms has not been clearly established. Therefore, this study investigated the spatiotemporal pattern of atrophy propagation in PD, its interindividual variability, and its relationship with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 control subjects were acquired at up to 15 time points per subject and over an observation period of up to 8.8 years (mean: 3.7 years). MR images were analyzed using deformation-based morphometry (DBM) to measure region volumes and their longitudinal changes. Differences in these regional volume data between patients and control subjects and their associations with clinical symptoms were calculated.
At the beginning of the study, the researchers found that the volumes of several brain regions were smaller in the PD patients than in the control group, while some regions were enlarged in the patients' brains, presumably due to compensatory effects. Over time, the difference between the groups became larger and more pronounced: the brain volumes of the Parkinson's patients decreased almost twice as fast as those of the control group, especially in the grey matter. The temporal and occipital lobes, adjacent parts of the inferior parietal lobe and ventral parts of the frontal lobe were most affected by this volume decrease.
Detailed analysis of which parts of the brain changed over time was performed using neuroanatomical atlases, most notably the Julich Brain Atlas, which is freely available through the EBRAINS infrastructure. This detailed anatomical analysis revealed a very specific regional pattern of volume changes in Parkinson's patients that differed from that of healthy ageing. The researchers found that volume reductions in cortical areas, amygdala, and basal forebrain correlated with worsening clinical symptoms in PD patients.
Thus, longitudinal DBM appears to already map the progression of neuropathological changes in vivo, providing a tool to further explore PD.
Regional changes of brain structure during progression of idiopathic Parkinson's disease – A longitudinal study using deformation based morphometry
Peter Pieperhoff
Added on: 07-06-2022
Neurospheres for developmental neurotoxicity tests
2022
IUF-Leibniz Research Institute for Environmental Medicine, Duesseldorf, Germany
In this study, the neurosphere assay, a high-content assay for developmental neurotoxicity (DNT) evaluation, is scientifically validated using a mechanistic rationale approach. The neurosphere assay is based on human primary neural progenitor cells which are cultivated as neurospheres that have the potential to differentiate into brain effector cells including neurons, astrocytes and oligodendrocytes. The assay assesses the neurodevelopmental key events: progenitor cell proliferation, radial glia cell migration, neuronal differentiation, neurite outgrowth, oligodendrocyte differentiation, and thyroid hormone-dependent oligodendrocyte maturation.
A validation process was performed based on 1) describing the relevance of the respective endpoints for brain development, 2) the confirmation of the cell type-specific morphologies observed in vitro, 3) expressions of cell type-specific markers consistent with those morphologies, 4) appropriate anticipated responses to physiological pertinent signalling stimuli and 5) alterations in specific in vitro endpoints upon challenges with confirmed DNT compounds.
The results demonstrate that the neurosphere assay is suitable for DNT evaluation for regulatory purposes.
Scientific validation of human neurosphere assays for developmental neurotoxicity evaluation
Ellen Fritsche
Added on: 07-26-2022
Organoids with vascular networks
2022
Katholieke Universiteit Leuven, Leuven, Netherlands
In this study, a human pluripotent stem cell (hPSC)-based approach to generate organoids which interact with vascular cells in a spatially defined manner is described. The spatial interaction between organoid and vasculature is enabled by the use of a 3D printed microfluidic chip which allows for a sequential and developmentally matched co-culture system. It is demonstrated that on-chip hPSC-derived pericytes and endothelial cells sprout and self-assemble into organized vascular networks. Cerebral organoids are used as a model system to explore interactions with this de novo-generated vasculature. Upon co-development, vascular cells physically interact with the cerebral organoid and form an integrated neurovascular organoid. The 3D printing-based platform is designed to be compatible with any organoid system and is an easy and cost-effective way to vascularize organoids.
Engineering neurovascular organoids with 3D printed microfluidic chips
Adrian Ranga
Added on: 05-27-2022
"Math neurons" identified in the brain
2022
University of Bonn Medical Center, Bonn, Germany(1)
University of Tübingen, Tübingen, Germany(2)
University of Tübingen, Tübingen, Germany(2)
Arithmetic is a cornerstone of scientifically and technologically advanced human culture, but its neuronal mechanisms are poorly understood. Here, the researchers explored the brain mechanisms involved in simple arithmetic operations by recording single-neuron activity from the medial temporal lobe of human subjects performing additions and subtractions. Five women and four men who had electrodes implanted in their brains due to epilepsy treatment participated in the study. The authors found that different neurons fired during additions than during subtractions. This suggests different cognitive functions for medial temporal lobe regions in arithmetic. This study marks an important step towards a better understanding of one of our most important symbolic abilities, namely calculating with numbers.
Neuronal codes for arithmetic rule processing in the human brain
Florian Mormann(1), Andreas Nieder(2)
Added on: 03-10-2022
A potential new way of preventing Alzheimer’s disease
2022
Laval University, Quebec, Canada
Toxic β-amyloid peptides induce neuron death, memory problems, and Alzheimer's disease (AD) development. Several amyloid precursor protein (APP) mutations increase the risk of developing early-onset AD. However, the A673T mutation identified in the Icelandic population prevents AD development by reducing the cleavage of APP by β-secretase. In this study, the researchers inserted the A673T mutation in human cells using the CRISPR prime editing (PE) technique. They show that PE is a promising approach for introducing the A673T mutation precisely without mutating nearby nucleotides.
Insertion of the Icelandic mutation (A673T) by prime editing: a potential preventive treatment for familial and sporadic Alzheimer's disease
Jacques P. Tremblay
Added on: 03-10-2022
Assessing astrocyte reactivity using neural organoids
2022
Houston Methodist Research Institute, Houston, USA
Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, the researchers devised a straightforward bioengineered neural organoid culture approach entailing transcription factor-driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modelling and preclinical drug testing.
Assessing Gq-GPCR–induced human astrocyte reactivity using bioengineered neural organoids
Robert Krencik
Added on: 11-28-2022
Gut bacteria linked to infant sleep patterns
2022
University Hospital Zurich, Zurich, Switzerland
Sleep disorders have been linked to alterations of gut microbiota composition in adult humans, but it is unclear how this link develops. With longitudinal assessments of 162 healthy infants, the authors present a so far unrecognized sleep-brain-gut interrelationship. They report a link between sleep habits, gut microbiota, sleep neurophysiology and development. These results demonstrate the dynamic interplay between sleep, gut microbiota, and the maturation of the brain and behaviour during infancy, which aligns with the newly emerging concept of a sleep-brain-gut axis. Importantly, sleep and gut microbiota represent promising health targets since both can be modified non-invasively. As many adult diseases root in early childhood, leveraging protective factors of adequate sleep and age-appropriate gut microbiota in infancy could constitute a health-promoting factor across the entire human lifespan.
From Alpha diversity to Zzz: Interactions among sleep, the brain, and gut microbiota in the first year of life
S. Kurth
Added on: 03-16-2022
Hyaluronan-laminin hydrogels for 3D neuronal cell culture
2022
KTH Royal Institute of Technology, Stockholm, Sweden(1)
Linköping University, Linkoping, Sweden(2)
Linköping University, Linkoping, Sweden(2)
In this work, a 3D bioprinting-compatible modular hyaluonan-based hydrogel system was developed that allows for convenient integration and efficient retention of recombinant laminin, which enhances the survival, proliferation, and differentiation of neuroepithelial stem cells. Laminin presenting hydrogels were cross-linked by copper-free click chemistry, thereby enabling the tuning of material properties and creation of biologically relevant microenvironments.
The resulting hydrogels supported encapsulation and culture of both, human neuroblastoma cells (SH-SY5Y) and human induced pluripotent stem cell (hiPSC)-derived neuroepithelial stem cells.
The tunable rheological properties of the hydrogels provided a protective effect on the neuroepithelial stem cells during syringe extrusion in an in vitro model for cell injection therapy. In addition, 3D bioprinting of the cell-laden hydrogels allowed for the fabrication of structurally well-defined constructs with high cell viabilities, facilitating the development of tissue and disease models.
Bioorthogonally cross-linked hyaluronan-laminin hydrogels for 3D neuronal cell culture and biofabrication
Anna Herland(1), Daniel Aili(1, 2)
Added on: 08-31-2022
Machine-assisted discovery toward sustained neural regeneration
2022
Princeton University, Princeton, USA(1)
The State University of New Jersey, Piscataway, USA(2)
The State University of New Jersey, Piscataway, USA(2)
Shortly after spinal cord injury, a secondary inflammatory cascade creates dense scar tissue that can inhibit or prevent nerve tissue regeneration. The enzyme ChABC degrades scar tissue after spinal cord injury and promotes tissue regeneration. However, it is highly unstable at human body temperature and loses all activity within a few hours. In this study, ChABC was stabilized by formulation through the use of artificial intelligence (AI) and robotics such that its activity was prolonged by a large amount.
Synthetic copolymers are able to wrap around enzymes such as ChABC and stabilize them in hostile microenvironments. To stabilize the enzyme, researchers used an AI-driven approach with liquid robots to synthesize numerous copolymers and test their ability to stabilize ChABC and maintain its activity at human body temperature for up to a week.
Machine-assisted discovery of chondroitinase ABC complexes toward sustained neural regeneration
Michael A. Webb(1), Adam J. Gormley(2)
Added on: 09-12-2022
Molecular pathway shared by two neurodegenerative disorders found
2022
National Institutes of Health (NIH), Bethesda, USA(1)
UCL Queen Square Institute of Neurology, London, United Kingdom(2)
UCL Queen Square Institute of Neurology, London, United Kingdom(2)
This study elucidates how the mislocalization of the TDP-43 protein alters the genetic instructions for UNC13A. Amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) are two neurodegenerative disorders often characterized by mislocalization of the TDP-43 protein, where instead of being primarily located in the nucleus of the cell, it forms aggregates outside the nucleus. Using human iPSC-derived neurons, as well as postmortem human brain and spinal cord tissue, the study demonstrates a genetic link between the loss of nuclear TDP-43 function and disease. It also reveals the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. According to the researchers, this discovery could provide a possible therapeutic target for ALS, FTD and other forms of dementia.
TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A
Michael E. Ward(1), Pietro Fratta(2)
Added on: 03-16-2022
Recovery of motor function after paralysis by activity-dependent neuromodulation
2022
Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland(1)
Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland(2)
Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland(2)
Epidural electrical stimulation (EES), which targets the dorsal nerve roots of the lumbosacral segments, allows people with spinal cord injuries (SCI) to walk again. However, EES is performed with multielectrode paddle leads that were originally designed for the dorsal column of the spinal cord. In this study, it was hypothesized that an array of electrodes targeting the system of dorsal nerve roots involved in leg and trunk movements would result in better efficacy and restore a greater variety of motor activities after the most severe damage. To test this, a computerized system was developed to determine the optimal placement of electrodes on a new paddle lead and to guide neurosurgical positioning. Software assisted in the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. As part of an ongoing clinical trial, these neurotechnologies were tested in three individuals with complete sensorimotor paralysis. Here, the activity-specific stimulation programs enabled the patients to stand, walk, bike, swim, and control trunk movements within one day. Accordingly, the method developed here resulted in sufficient improvement in activities, supporting people with SCI in their daily mobility.
Activity-dependent spinal cord neuromodulation rapidly restores trunk and leg motor functions after complete paralysis
Jocelyne Bloch(1), Grégoire Courtine(2)
Added on: 09-12-2022
Blood-brain barrier serves as a CNS entry route for SARS-CoV-2
2022
Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Hamburg, Germany(1)
University Medical Center Hamburg-Eppendorf, Hamburg, Germany(2)
University Medical Center Hamburg-Eppendorf, Hamburg, Germany(2)
Although SARS-CoV-2 has been detected in the brain tissue of patients, its entry pathways and resulting consequences are not well understood. In this study, the researchers demonstrate a distinct upregulation of interferon signalling pathways in the neurovascular unit in lethal COVID-19. Examined the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection and found that BCECs were infected and recapitulated the transcriptional changes detected in vivo. While BCECs were unaffected in their paracellular tightness, SARS-CoV-2 was found in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of the virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Taken together, the data demonstrate that SARS-CoV-2 enters the brain via the BBB and leads to increased interferon signalling.
The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2
Ole Pless(1), Susanne Krasemann(2)
Added on: 07-07-2022
Engineering brain assembloids to interrogate human neural circuits
2022
Stanford University, Stanford, USA
Studying the developmental processes of neural circuits in the human nervous system remains difficult due to the limited availability of tissue that can be maintained functional in vitro for extended periods of time. In this protocol, we describe approaches to model long-distance neuronal connectivity in human brain assembloids. We show how 3D spheroids resembling specific areas of the nervous system are generated, and how they are then physically integrated to enable axonal projections and synaptic connections. In addition, a series of experiments are described, including viral labelling and retrograde tracking, live 3D imaging of axon projection, and optogenetics combined with calcium imaging and electrophysiological recordings to probe and manipulate circuitry in the assembloids. The approaches described may be useful in deciphering human-specific aspects of neuronal circuit assembly and in modelling neurodevelopmental disorders with patient-derived cells.
Engineering brain assembloids to interrogate human neural circuits
Sergiu P. Paşca
Added on: 09-12-2022
Measurement system for bioreactors with dynamic flow for investigating blood-brain barrier models
2022
University Hospital Wuerzburg, Wuerzburg, Germany
Electrochemical impedance spectroscopy (EIS) is a non-invasive, reliable and efficient method to analyze the barrier integrity of in vitro tissue models, so far under static conditions. Here, we present a bioreactor system that allows automated, continuous, and noninvasive monitoring of cellular barrier integrity during dynamic culture. Polydimethylsiloxane (PDMS) casting and 3D printing were used to fabricate the bioreactors. To test the monitored bioreactor system, in vitro models of the blood-brain barrier (BBB) were cultured from human pluripotent stem cells (hiPSC) for up to 7 days. The transendothelial/epithelial resistance (TEER) level was found to decrease over time, which was also true for the static control culture. This versatile system offers the possibility to be used for various dynamic tissue cultures that require a non-invasive monitoring system for barrier integrity.
Online measurement system for dynamic flow bioreactors to study barrier integrity of hiPSC-based blood–brain barrier in vitro models
Jihyoung Choi, Antje Appelt-Menzel
Added on: 07-07-2022
Patient study to investigate dynamic processes in the brain
2022
Max Planck Institute of Psychiatry, Munich, Germany
So far, little is known about the dynamic processes in the brain during acute stress, as research usually focuses on which areas are active at a given time.
Here, 217 subjects with and without affective disorders such as depression and anxiety disorders were observed over the entire period of a stressful situation (solving a math problem under time pressure). In addition to magnetic resonance imaging images, the researchers measured the stress hormone cortisol and heart rate.
The dynamic response of the networks in the subjects' brains during the stressful situation varied. Not only were changes found in the communication between brain regions, but also a dynamic process: different networks acted differently during acute stress. From this, the scientists could determine how susceptible a person was to a negative mood and how this increased his or her risk of mental illness. The results of the study thus show how different brain regions interact and how their communication changes over the course of the situation. These findings could be significant for the development of individual diagnoses and therapies.
Spatiotemporal dynamics of stress-induced network reconfigurations reflect negative affectivity
Elisabeth B. Binder, Anne Kühnel
Added on: 11-21-2022
Analyses of human midbrain tissues reveal Parkinson's disease mechanisms
December 2021
University of Luebeck, Luebeck, Germany(1)
University of Luxembourg, Luxembourg, Luxembourg(2)
University of Luxembourg, Luxembourg, Luxembourg(2)
Parkinson’s disease is characterized by a progressive loss of dopaminergic neurons, but the involved mechanisms remain largely unknown. A large genome-wide association study assessed the cell type-specific risk for Parkinson’s disease. Using post-mortem midbrain samples of patients, the contribution of all cell types was analysed by single-nuclei RNA sequencing. The same tissues were immunolabelled for validation of the outcomes. A specific neuronal cell cluster was identified as being exclusively present in Parkinson’s disease midbrains.
Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state
Malte Spielmann(1), Anne Grünewald(2)
Added on: 12-06-2022
Modelling ischemic stroke in a triculture neurovascular unit on-a-chip
CompanyDecember 2021
MIMETAS BV, Oegstgeest, Netherlands
In ischemic stroke, the function of the cerebral vasculature formed by the so-called neurovascular unit (NVU) is impaired. Complex human in vitro models of the NVU have been lacking for a better understanding of the mechanisms involved in NVU dysfunction and recovery.
Here, the researchers describe the development of a human NVU on-a-chip model with a platform that allows the parallel cultivation of 40 chips. The model consists of a perfused vessel with primary human brain endothelial cells in co-culture with astrocytes and neurons derived from induced pluripotent stem cells. Ischemic stroke was mimicked with a triple approach combining chemical hypoxia, hypoglycemia, and interrupted perfusion. The model thereby showed spontaneous neuronal activity as well as physiological barrier function. Exposure to the toxic substance staurosporine disrupted the endothelial barrier, reducing transepithelial electrical resistance and increasing permeability to sodium fluorescein. Under conditions mimicking stroke, brain endothelial cells also showed greatly reduced barrier function.
The results indicate that the model may be useful for basic studies of NVU function in stroke and other neurological diseases, for the investigation of potential therapies, and, because of its potential automation, for drug screening.
Modeling ischemic stroke in a triculture neurovascular unit on-a-chip
Nienke R. Wevers
Nienke R. Wevers et al. Fluids and Barriers of the CNS 2021 [171]
Physicians Committee for Responsible Medicine [172]
Added on: 02-01-2022
Personalised brain models to improve depression treatment
December 2021
Aix-Marseille Université, Marseille, France(1)
Ewha Womans University, Seoul, South Korea(2)
University of Calgary, Calgary, Canada(3)
Ewha Womans University, Seoul, South Korea(2)
University of Calgary, Calgary, Canada(3)
Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient. The engagement of specific fibre tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here a computational framework that can explore each individual's brain response characteristics was provided, elicited by selective stimulation of fibre tracts. A novel personalised in silico approach was used, the Virtual Big Brain, which makes use of high-resolution virtual brain models at an mm-scale and explicitly reconstructs more than 100,000 fibre tracts for each individual. Each fibre tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient. This study provides evidence for the capacity of personalised high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalised optimization of brain stimulation.
High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways
Viktor K. Jirsa(1), Sora An(2), Andrea B. Protzner(3)
Added on: 05-12-2022
Episodic memory processing studied using patient recordings
November 2021
University of Texas Southwestern, Dallas, USA
Episodic memory requires linking objects to a temporal context, a process for which the medial temporal lobe (MTL) is crucial. This study used records from 27 people who underwent surgery for intractable epilepsy. 103 memory-sensitive neurons in the hippocampus and entorhinal cortex were identified, whose firing rates predicted successful encoding of episodic memory while subjects performed a verbal free recall task. These neurons exhibit important properties. First, as predicted by the temporal context model, they show recovery of firing patterns observed during encoding at the time of retrieval. The extent of retrieval predicted the tendency of subjects to group the retrieved memory items according to the serial position of the input. In addition, it was found that the spiking activity of these neurons was tied to the phase of hippocampal theta oscillations, but that the middle phase of spiking activity shifted between encoding and retrieval of memories. This unique observation is consistent with the predictions of the Separate Phases at Encoding And Retrieval (SPEAR) model. Taken together, the properties of memory-sensitive neurons characterize direct electrophysiological mechanisms for the representation of contextual information in human MTL.
Neurons in the human medial temporal lobe track multiple temporal contexts during episodic memory processing
Bradley Lega
Added on: 02-01-2022
Highly efficient gene editing in human cell lines
November 2021
Hannover Medical School, Hannover, Germany
This study investigates the influence of the design of prime editing guide RNA (pegRNA) and different transfection protocols on CRISPR prime-editing, which is a novel variant of the CRISPR/Cas9 method (known as the so-called genetic scissor) allowing for targeted gene editing. In order to obtain a fast read-out, a novel fluorescence reporter system was developed, which allows for the estimation of gene correction and defective editing. Human kidney cells (HEK293) and human induced pluripotent stem cells (hiPSC) were used to compare and optimize protocols for editing and transfection.
Finally, the developed protocol was used for rapid and efficient editing of amyotrophic lateral sclerosis (ALS)-associated mutation in a gene of patient-derived hiPSC.
The system can be used in disease modelling by employing patient-derived parental cells and syngenic gene-corrected cells, and can thereby e.g. help to better understand the biological mechanisms associated with rare hereditary mutations.
A selectable all‑in‑one CRISPR prime editing piggyBac transposon allows for highly efficient gene editing in human cell lines
Tobias Cantz, Reto Eggenschwiler
Added on: 08-24-2022
Investigating olfactory dysfunction in COVID-19
November 2021
KU Leuven, Leuven, Belgium(1)
Max Planck Research Unit for Neurogenetics, Frankfurt, Germany(2)
Max Planck Research Unit for Neurogenetics, Frankfurt, Germany(2)
This study investigates the mechanisms underlying the loss of smell as a symptom of COVID-19. Therefore, samples of respiratory and olfactory mucosae and whole olfactory bulbs were obtained endoscopically after the death of the patients.
70 COVID-19 patients, including patients that died a few days after infection during the replication phase of the virus, and 15 control cases were included in the study. RNA of tissue sections was investigated via in-situ hybridization and immunohistochemistry was performed for codetection of proteins. Moreover, whole-transcriptome profiling was done. No evidence for infection of olfactory sensory neurons and the tissue of the olfactory bulb was found.
Thus, SARS-CoV-2 does not appear to be a neurotropic virus and it is postulated that a transient insufficient support from infected sustentacular cells triggers olfactory dysfunction in COVID-19. This may yield strategies for therapeutic interventions for olfactory dysfunction in COVID-19.
Visualizing in deceased COVID-19 patients how SARS-CoV-2 attacks the respiratory and olfactory mucosae but spares the olfactory bulb
Laura Van Gerven(1), Peter Mombaerts(2)
Added on: 01-06-2023
Investigation of the role of epigenetics in amyotrophic lateral sclerosis
November 2021
Hannover Medical School, Hannover, Germany
This study investigates the role of epigenetics in amyotrophic lateral sclerosis (ALS). Therefore, ALS patient-derived induced pluripotent stem cells (iPSCs) and healthy control-derived iPSCs were generated and characterized. Neural progenitor cells from healthy control cell lines and ALS cell lines, carrying a mutation in the fused in sarcoma (FUS) gene, were differentiated into motor neurons. These motor neurons showed typical ALS pathology with cytoplasmic FUS aggregates. Expression and promoter methylation of the FUS gene and expression of DNA methyltransferases were analyzed and compared to healthy control cell lines.
The described approach can be used to investigate epigenetic modification as novel therapeutic targets.
Methylation and expression of mutant FUS in motor neurons differentiated from induced pluripotent stem cells from ALS patients
Susanne Petri
Added on: 08-23-2022
Single cell transcriptomics to reveal pathological pathways in ALS
November 2021
University of Exeter, Exeter, United Kingdom
Amyotrophic lateral sclerosis is a neurodegenerative disease driven by the loss of motor neurones. Here SOD1 E100G amyotrophic lateral sclerosis patient-derived induced pluripotent stem cells were used to perform single-cell transcriptomics analysis to identify signalling pathways related to the pathological outcome in dysfunctional neurones. The results showed several pathways and transcriptional factors leading to gene expression dysregulation, building an ALS-relevant transcriptional network map. SMAD2, a downstream effector of TGF-beta, was elucidated as a critical factor in SOD motor neurone degeneration. Moreover, TGF-beta was activated in different variations of amyotrophic lateral sclerosis, both familiar and sporadic cases. According to these findings, inhibition of TGF-beta improved diseased SOD1 motor neurone survival. Overall, the researchers demonstrate the utility of single-cell transcriptomics to uncover pathological pathways in neurodegenerative diseases, and this allows them to identify several SOD1-associated targets in perturbed motor neurone transcriptional networks.
Single-cell transcriptomics identifies master regulators of neurodegeneration in SOD1 ALS iPSC-derived motor neurons
Akshay Bhinge
Added on: 11-29-2021
Brain organoids to study potential gene–environment interactions
October 2021
Johns Hopkins University, Baltimore, USA
This study compares brain organoids containing a normal version of the gene CHD8 with those containing the ASD high-risk mutation CHD8+/-. CHD8 is one of more than 50 genes associated with higher autism spectrum syndrome (ASD) risk.
To test whether the pesticide chlorpyrifos (CPF), which has been linked as an environmental risk factor for ASD, disrupts similar signalling pathways as the mutation, which could indicate a synergistic interaction, both types of brain organoids were exposed to this pesticide for 24 hours. The researchers found that exposure to CPF reduced CHD8 protein levels more than the mutation alone. The pesticide also enhanced the effect of the mutation on several autism-related metabolites and neurotransmitters. In addition, pesticide exposure reduced neurite growth in both brain organoid species, indicating a disruption of neuronal functionality.
The fact that exposure to CPF further reduced CHD8 protein levels in the mutant cells suggests that the gene and the pesticide may have similar molecular targets. The observed reduction in CHD8 protein levels and neurite growth supports the possibility of more severe symptoms in CHD8 mutation carriers with higher CPF exposure.
Autism in three dimensions: using brain organoids to study potential gene–environment interactions
Lena Smirnova
Added on: 11-05-2021
Brain-model for Parkinson´s disease
CompanyOctober 2021
Emulate Inc., Boston, USA(1)
Harvard Medical School, Boston, USA(2)
Harvard Medical School, Boston, USA(2)
A human brain-chip representative of the substantia nigra area of the brain, the area predominantly affected in Parkinson´s disease, was developed. It contains human dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow, thereby recreating the vascular-neuronal interface. A model of neurodegenerative diseases characterized by the accumulation of aggregated α-synuclein (synucleinopathies) was created. Therefore, human α-synuclein pre-formed fibrils were introduced within the brain channel of the chip. It was demonstrated that the model replicates pathological key aspects observed in human Parkinson´s disease, including accumulation of α-Synuclein, mitochondrial dysfunction, neuroinflammation and compromised blood-brain barrier function. The human α-synuclein fibril-induced disease model could provide a model for recapitulating complex pathophysiological features of Parkinson´s disease, may enable research of the dynamics of cell-cell interactions in human synucleinopathies, and serve as a testing platform for target identification and validation of novel therapeutics.
Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption
Iosif Pediaditakis(1), Katia Karalis(2)
Added on: 03-31-2022
Gene therapy rescues the pathological phenotype in retinal organoids
October 2021
University of California San Francisco, San Francisco, USA
Leber congenital amaurosis caused by CRX mutations is characterised by dysfunction and loss of photoreceptors at the early stages of the disease. Thus, a robust in vitro model could enhance the design of gene-editing-based therapies. Here, patients derived human induced pluripotent stem cells with a dominant disease-causing mutation in CRX were used to develop retinal organoids that can reproduce key physiopathological features. The results showed that diseased organoids recapitulate several characteristics of the in vivo pathology, like immature and dysfunctional photoreceptor cells. Furthermore, CRISPR/Cas9-based gene editing was used to knock out the mutant CRX and this led to a partial improvement of photoreceptor phenotype. Overall, the researchers demonstrate the viability of pluripotent stem cells-based organoids to investigate dominant genetic diseases and suggest a potential gene therapy strategy to improve the pathological phenotype.
Allele-specific gene editing to rescue dominant CRX-associated LCA7 phenotypes in a retinal organoid model
Deepak A Lamba
Added on: 11-29-2021
Studying human neural development is challenging as samples are rare and difficult to obtain. A new and reliable model for neural tube morphogenesis was developed using the self-organizing properties of human pluripotent stem cells, directed by micropatterning on an organ-on-a-chip device and minimal morphogenetic compounds. The researchers could recapitulate neural tube closure, the developing neuroectoderm, and neural crest and surface ectoderm populations with proper migration patterns. This tool offers exciting perspectives for neural tube defect modelling.
Human neural tube morphogenesis in vitro by geometric constraints
Added on: 10-25-2022
Mini brains to study motor neuron disease and frontotemporal dementia
October 2021
University of Cambridge, Cambridge, United Kingdom
Amyotrophic lateral sclerosis overlapping with frontotemporal dementia (ALS/FTD) is a fatal and currently untreatable disease characterized by rapid cognitive decline and paralysis. Elucidating the initial cellular pathologies is central to developing therapeutic targets, but it is not possible to obtain samples from presymptomatic patients. Here, the researchers develop a long-term human cortical organoid (CO) model that accurately recapitulates the early molecular pathology of ALS/FTD. COs were grown from iPSCs derived from patients with ALS/FTD carrying the C9ORF72 mutation (C9 ALI-COs). This mutation is useful for modelling ALS/FTD as it causes a variety of pathologies in both sporadic and inherited forms of the disease. Using ALI-CO discs cultured from the organoids, ALI-COs are shown to form consistent microarchitecture and disease-relevant phenotypes. Furthermore, it was found that C9 ALI-COs, although lacking microglia and vasculature, exhibit astroglia- and neuron-specific perturbations. These results demonstrate that hiPSC-derived ALI-COs provide a reproducible platform with the necessary longevity and maturity to study ALS/FTD, thereby revealing early and targeted cellular vulnerabilities relevant to presymptomatic clinical stages.
Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology
Gabriel Balmus, András Lakatos
Added on: 11-09-2021
Particulate matter damages cognitive performance
October 2021
University of Rostock, Rostock, Germany
In the present study, the effects of particulate matter on lung function and cognitive performance of 49,705 people were investigated in long-term cohorts. The people all lived in areas with relatively low levels of air pollution. Furthermore, socio-demographic characteristics such as age, gender, education, existing pre-existing conditions and much more were taken into account in the evaluation of the results. The Cogstate Brief Battery (CBB), a validated computer-aided method, was used to assess the cognitive performance of the participants. The results showed that higher exposure to particulate matter is significantly associated with slower cognitive processing time (CPT). By means of mediation analyses, it was investigated whether the neurotoxicological pollutants reach the brain directly via the olfactory nerve or the bloodstream, or are indirectly mediated by lung function. This showed that particularly fine particles predominantly follow the direct path and even small amounts are sufficient to induce cognitive impairment. Furthermore, the hypothesis was confirmed that air pollutants enter the lungs by inhalation, which impairs lung function and can lead to pneumonia. On the basis of the results, further ways in which pollutants can specifically damage organs are now to be investigated.
Long-term exposure to fine particulate matter, lung function and cognitive performance: A prospective Dutch cohort study on the underlying routes
Benjamin Aretz
Added on: 08-17-2022
Viral diseases promote the spread of neurodegenerative diseases
October 2021
Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
Neurodegenerative diseases are characterized at the cellular level by misfolding proteins that form aggregated complexes and progressively infect the surrounding cell tissue. The transport mechanism of protein complexes into neighbouring cells is still unexplored. The research group of the present study suspects that the propagation of the aggregates takes place via direct cell contact or receptor-ligand-mediated transport in extracellular vesicles (EV). Therefore the effect of various viral glycoproteins in several cell models was investigated. In the cell cultures, which were additionally infected with viral enzymes, there was an accelerated invasion of the protein aggregates into the healthy neighbouring cells. The results of the study support the hypothesis that viral diseases have a significant influence on the development of neurodegenerative diseases. The study thus provides new findings of high relevance for further research into incurable diseases such as Alzheimer's or Parkinson's.
Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions
Ina M. Vorberg
Added on: 08-08-2022
Neuronal model of the sensation of mechanical stimuli
2021
Hannover Medical School, Hannover, Germany
Within this study, a robust differentiation protocol for the generation of certain human somatosensory mechanoreceptor-like neurons (termed SZ-LTMRs), from induced pluripotent stem cells (iPSCs)-derived neuronal precursor cells is described.
The SZ-LTMRs express functional mechano-transducers Piezo1 and Piezo2, corresponding to the in vivo situation. They are also able to convert mechanical stimuli into electrical signals and have specialized axon termini. The iPSC-derived cells can be used as a model of sensory nerve endings, and provide an in vitro model to study the role of Piezo1 and Piezo2 in mechanosensation. The model is expected to be useful to study human mechanotransduction.
Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2
Abel Viejo-Borbolla, Shuyong Zhu
Added on: 08-18-2022
Organoid model of the forebrain shows typical changes for autism
2021
Columbia University, New York, USA
Forebrain organoids generated from induced pluripotent stem cells of patients with symptomatic form of Autism Spectrum Disorder (ASD) with a mutation in CNTNAP2 were utilized, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides an opportunity for further mechanistic inquiry and the development of new therapeutic strategies for ASD.
Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder
Sander Markx, Bin Xu
Added on: 03-01-2022
Synthesis of imagined speech processes from minimally invasive recordings of neural activity
2021
Maastricht University, Maastricht, Netherlands(1)
University of Bremen, Bremen, Germany(2)
University of Bremen, Bremen, Germany(2)
Speech neuroprosthetics aim to provide a natural communication channel to individuals who are unable to speak due to physical or neurological impairments. Real-time synthesis of acoustic speech directly from measured neural activity could enable natural conversations and notably improve quality of life, particularly for individuals who have severely limited means of communication. Recent advances in decoding approaches have led to high-quality reconstructions of acoustic speech from invasively measured neural activity. However, most prior research utilizes data collected during open-loop experiments of articulated speech, which might not directly translate to imagined speech processes. Here, an approach that synthesizes audible speech in real-time for both imagined and whispered speech conditions was presented. Using a participant implanted with stereotactic depth electrodes, the authors were able to reliably generate audible speech in real-time. The decoding models rely predominately on frontal activity suggesting that speech processes have similar representations when vocalized, whispered, or imagined. While reconstructed audio is not yet intelligible, the real-time synthesis approach represents an essential step toward investigating how patients will learn to operate a closed-loop speech neuroprosthesis based on imagined speech.
Real-time synthesis of imagined speech processes from minimally invasive recordings of neural activity
Christian Herff(1), Miguel Angrick(2)
Added on: 03-01-2022
A human brain organoid model for Alzheimer’s disease
2021
Beckman Research Institute of City of Hope, Duarte, USA
Alzheimer's disease (AD) is a progressive neurodegenerative disease. To date, there are no successful therapies, mainly due to the incomplete understanding of the complex pathophysiology of Alzheimer's disease, especially sporadic Alzheimer's disease (sAD). In this study, sAD is modelled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Since blood-brain barrier (BBB) leakage is a known risk factor for Alzheimer's disease, the brain organoids are exposed to human serum to mimic the consequences of BBB breakdown in the brains of Alzheimer's patients resulting from serum exposure. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid-beta aggregates (Aβ) and phosphorylated microtubule-associated tau proteins (p-tau), synaptic loss and impaired neuronal network. Serum exposure thereby increases Aβ and p-tau levels through enzyme induction. Furthermore, single-cell transcriptome analysis of brain organoids shows that serum exposure reduces synaptic function in both neurons and astrocytes and induces an immune response in astrocytes. The human brain organoid-based sAD model established in this study may provide a powerful platform for both mechanistic investigation and therapeutic development in the future.
Modeling sporadic Alzheimer's disease in human brain organoids under serum exposure
Yanhong Shi
Added on: 11-05-2021
Human brain organoids develop eyes
2021
Heinrich-Heine-Universität, Dusseldorf, Germany
Here, iPSC technology is used to grow mini-brains in order to study inherited eye diseases. With cells from four iPSC donors, brain organoids were grown and on day 20, retinoic acid was added. After 30 days of cultivation, the organoids assembled optical vesicles, which developed within 60 days to visible structures. The optic vesicle-containing brain organoids (OVB-organoids) show various structures which are typical for the eye like primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. They as well display synapsin-1, CTIP-positive myelinated cortical neurons, and microglia. The organoids even show photosensitive activity when triggered by various light intensities, which could be reset by transient photobleaching. The OVB-organoids possess the ability to self-organize forebrain-associated primitive sensory structures and thus can be used as a model to study eye development and underlying causes of eye diseases.
Human brain organoids assemble functionally integrated bilateral optic vesicles
Jay Gopalakrishnan
Added on: 09-09-2021
Human iPSC-derived model to study myelin disruption
2021
Johns Hopkins Bloomberg School of Public Health, Baltimore, USA(1)
University of Lausanne, Lausanne, Switzerland(2)
University of Lausanne, Lausanne, Switzerland(2)
Myelin is critically important in the central nervous system, and its disruption is associated with a variety of neurological and neurodegenerative diseases. Recently, 3D cell cultures derived from human iPSC have become available that can partially reproduce the myelination process. Here, the researchers further refine a human iPSC-derived 3D brain organoid model ("BrainSpheres") that contains a high percentage of myelinated axons by using multiple measurement methods to study myelination disruption. Myelination was assessed by quantification of immunostaining/confocal microscopy of colocalized myelin-based protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also determined by Western blot. To evaluate the relevance of the BrainSphere model for the study of myelination and demyelination processes, compounds capable of inducing developmental neurotoxicity by disrupting myelin are used. The results show that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested decreased myelination, while ibuprofen (negative control) had no effect. Thus, the presented method allows quantification of myelin disruption and provides reference substances for chemically induced myelin disruption.
Human iPSC-derived model to study myelin disruption
Helena T. Hogberg(1), David Pamies(2)
Added on: 10-06-2021
Oversupply of cholesterol to APOE4 astrocytes leads to amyloidosis in human neurons
2021
DGIST, Daegu, South Korea
The E4 allele of APOE is a major genetic risk of developing sporadic Alzheimer's disease. However, the mechanisms linking this gene variant to the development of pathological hallmarks in patients neurones remains unclear. Here, neurones and astrocytes were generated from isogenic human induced pluripotent stem cells carrying the E3 or E4 alleles to investigate the influence of APOE4 astrocytes on neuronal amyloid-beta production. The results showed that paracrine signalling of diseased astrocytes increased the production of amyloid precursor protein and secretion of amyloid-beta in neurones. Furthermore, modulation of cholesterol levels demonstrated that cholesterol secretion from APOE4 astrocytes was necessary and sufficient to induce pathological outcomes through the formation of lipid rafts. Overall, the researchers reveal key pathological mechanisms involving APOE4 astrocytes-driven oversupply of cholesterol that lead to neuronal amyloidosis.
APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation
Jinsoo Seo
Added on: 11-29-2021
Vascularized glioblastoma on a chip
2021
University of Technology Sydney, Sydney, Australia
In this study, a 3D vascularized glioblastoma on-a-chip model has been developed by combination of a microfluidic system and 3D bioprinting. Glioblastoma cells and endothelial cells were printed separately into the tissue compartment of the device using distinct hydrogels as bioinks. The tissue compartment was surrounded by a circular vascular channel which was separated from the tissue compartment via a porous membrane. Endothelial cells were seeded into the vascular channel, resulting in a functional blood-brain-barrier. The model was tested under microgravity conditions resulting in a significant cell morphological response.
The glioblastoma-on-a-chip model could represent a meaningful biological tool for research in cancer mechanobiology and preclinical research in brain tumor therapy.
A 3D-bioprinted vascularized glioblastoma-on-a-chip for studying the impact of simulated microgravity as a novel pre-clinical approach in brain tumor therapy
Joshua Chou
Added on: 04-05-2023
A personalised human iPSC model for chemotherapy-induced neurotoxicity
2021
Charité - Universitätsmedizin Berlin, Berlin, Germany
Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, potentially irreversible adverse effect of cytotoxic chemotherapy often leading to a reduction or discontinuation of treatment which negatively impacts patients' prognosis. To date, however, neither predictive biomarkers nor preventive treatments for CIPN are available, which is partially due to a lack of suitable experimental models. The authors, therefore, aimed to evaluate whether sensory neurons derived from induced pluripotent stem cells (iPSC-DSN) can serve as a human disease model system for CIPN. Treatment of iPSC-DSN with four neurotoxic drugs led to axonal blebbing and a dose-dependent decline of cell viability in clinically relevant ranges, which was not observed for non-neurotoxic compounds. Comparing sensory neurons derived from two different healthy donors, the authors found preliminary evidence that these cell lines react differentially to neurotoxic drugs as expected from the variable presentation of CIPN in patients. In conclusion, iPSC-DSN are a promising platform to study the pathogenesis of CIPN and to evaluate neuroprotective treatment strategies. In the future, the application of patient-specific iPSC-DSN could open new avenues for personalized medicine with individual risk prediction, choice of chemotherapeutic compounds and preventive treatments.
Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons
Wolfgang Boehmerle
Added on: 10-21-2021
Bioengineered optogenetic model of human neuromuscular junction
2021
Columbia University, New York, USA(1)
Gladstone Institutes, San Francisco, USA(2)
Gladstone Institutes, San Francisco, USA(2)
Functional human tissues derived from patient-specific induced pluripotent stem cells (hiPSCs) hold promise for controlled and systematic research into the progression, mechanisms, and treatment of musculoskeletal diseases. Here, the researchers describe a standardized method for producing an isogenic, patient-specific human neuromuscular junction (NMJ) that enables automated quantification of NMJ function to diagnose disease using a small blood serum sample and evaluate novel therapeutic modalities. By combining tissue engineering, optogenetics, microfabrication, optoelectronics, and video processing, a novel platform has been created for the precise study of human NMJ development and degeneration. The study demonstrates the utility of this platform for the detection and diagnosis of myasthenia gravis, an antibody-mediated autoimmune disease that disrupts NMJ function.
Bioengineered optogenetic model of human neuromuscular junction
Gordana Vunjak-Novakovic(1), Olaia F. Vila(2)
Added on: 10-04-2021
Computational method to analyse brain dynamics
2021
Universitat Pompeu Fabra, Barcelona, Spain
Nowadays, functional magnetic resonance imaging generates satisfactory representations of the brain. However, brain dynamics during different states remain unclear. Here, an analysis method using dimensionality reduction is developed to decode imaging data and elucidate spatiotemporal dynamics of brain activity in different states. The results elucidated nonlinear differences between different states and these data allowed the researchers to efficiently classify them. Moreover, further analysis of a subject group revealed a shared topology between individuals constrained by the brain state rather than the differences between participants. Overall, the researchers revealed the intrinsic manifold that describes brain dynamics and enables decoding and classifying different brain states.
Decoding brain states on the intrinsic manifold of human brain dynamics across wakefulness and sleep
Joan Rué-Queralt
Added on: 12-01-2021
Development of microglial-containing human brain organoids
2021
Rutgers University, Piscataway, USA
Microglia is an essential actor in brain physiology. In recent years, human pluripotent stem cells are surging as a reliable tool to generate specific cell types to incorporate in in vitro models. Nonetheless, there are still no optimised protocols to properly recapitulate microglia differentiation in in vivo brain development. Here, human pluripotent stem cells-derived neural and macrophage progenitor cells were used to generate region-specific brain organoids that contain microglia. The results showed that the generation of organoids had a controllable microglia ratio and that the microglial cells were physiologically functional. Moreover, Zika virus infection efficiently triggered microglial responses. Overall, the researchers establish a new protocol replicating in vivo neurodevelopment for the generation of organoids including microglia that could potentially be used to study microglial physiology and its role in neurological disorders.
Developing human pluripotent stem cell-based cerebral organoids with a controllable microglia ratio for modeling brain development and pathology
Ranjie Xu, Peng Jiang
Added on: 11-29-2021
In vitro model of serotonin neurons based on human pluripotent stem cells
2021
Soonchunhyang University, Cheonan, South Korea
Serotonin neurons are the major neuronal type present in the raphe nuclei and they can be divided into rostral and caudal groups. During neurodevelopment, serotonergic neurons develop from ventral hindbrain progenitors. Here, human pluripotent stem cells are differentiated into ventral-type neural progenitors and further maturated with specific factors related to hindbrain serotonin neurodevelopment to build a novel in vitro model of serotonin neurons. The results showed an efficiency of around 30%-40% of cells reproducing the serotonergic-neurone-phenotype, most of them with caudal rhombomere identity. Further modifications of the protocol allowed the generation of serotonin neuron-enriched hindbrain-like organoids. Overall, the researchers develop an in vitro model with neural cells that acquire serotonergic phenotype and have functional activity both in monolayer and organoid systems, which could be potentially used to investigate cellular mechanisms and/or perform drug development experiments.
Generation of caudal-type serotonin neurons and hindbrain-fate organoids from hPSCs
Jeong Kyo Yoon, Yun Kyung Lee, Jae-won Shim
Added on: 11-29-2021
Midbrain organoids for toxicity testing
2021
Max Planck Institute for Molecular Biomedicine, Muenster, Germany
In this study, an automated organoid model of the human midbrain was utilized to screen for the general neurotoxic and dopaminergic neuron-specific toxic effects of a library of 84 compounds including pesticides, drugs, flame retardants, and non-toxic controls. The toxic effects were evaluated on both, total cell viability and dopaminergic neurons. Follow-up dose-response experiments further confirmed the results of the primary screens. The method enables dissecting the toxicities of compound exposure to separate cellular subpopulations within human organoids at the single-cell level. Furthermore, the higher sensitivity in 3D culture was demonstrated in comparison to 2D cultures. The automated workflow is scalable and demonstrates the feasibility of quantitatively assessing cell-type-specific toxicity in human organoids in vitro.
Cell-type-specific high throughput toxicity testing in human midbrain organoids
Jan M. Bruder, Hans R. Schöler
Added on: 04-28-2022
Neural-perivascular assembloid reveals astrocyte maturation and SARS-CoV-2 neuropathology
2021
University of California San Diego, La Jolla, USA
Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here it is shown, that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral ‘replication hubs’, with viral spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new ‘assembloid’ model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue.
A human three-dimensional neural-perivascular ‘assembloid’ promotes astrocytic development and enables modeling of SARS-CoV-2 neuropathology
Joseph G. Gleeson, Aaron F. Carlin
Added on: 10-04-2021
Personalized sequencing for the noninvasive diagnosis of gliomas
2021
Cancer Centre Amsterdam, Amsterdam, Netherlands(1)
Cancer Research UK Cambridge Institute, Cambridge, United Kingdom(2)
University of Cambridge, Cambridge, United Kingdom(3)
Cancer Research UK Cambridge Institute, Cambridge, United Kingdom(2)
University of Cambridge, Cambridge, United Kingdom(3)
Glioma-derived cell-free DNA (cfDNA) is challenging to detect using liquid biopsy because quantities in body fluids are low. Here, the glioma-derived DNA fraction in cerebrospinal fluid (CSF), plasma, and urine samples from patients was determined, using sequencing of personalized capture panels guided by analysis of matched tumor biopsies. By sequencing cfDNA across thousands of mutations, identified individually in each patient’s tumor, tumor-derived DNA in the majority of CSF, plasma, and urine samples was detected. Further, cfDNA fragment sizes were analysed using whole-genome sequencing, in urine samples from 35 glioma patients, 27 individuals with non-malignant brain disorders, and 26 healthy individuals. cfDNA in the urine of glioma patients was significantly more fragmented compared to urine from patients with non-malignant brain disorders and healthy individuals. Machine learning models integrating fragment length could differentiate urine samples from glioma patients, suggesting possibilities for truly non-invasive cancer detection.
Fragmentation patterns and personalized sequencing of cell-free DNA in urine and plasma of glioma patients
Florent Mouliere(1), Richard Mair(2), Nitzan Rosenfeld(2), Kevin Brindle(3)
Added on: 10-04-2021
Role of genetic and environmental interactions in autism found in brain organoids
2021
Johns Hopkins University, Baltimore, USA
Using brain organoids differentiated from stem cells, exposure to a pesticide was shown to interact with a common gene mutation associated with autism.
Here, the pesticide chlorpyrifos, which has been reported to contribute to developmental neurotoxicity and autism risk, dramatically reduced the concentration of the protein CHD8 in the organoids. CHD8 is a regulator of gene activity that is important for brain development. Mutations in its gene that reduce CHD8 activity are among the strongest of the more than 100 genetic risk factors for autism identified to date.
In the study, the cells that make up the organoids were altered to lack one of the two normal copies of the CHD8 gene. This resulted in a significant, but not complete, weakening of the CHD8 gene's activity, similar to that seen in people who have CHD8 mutations and autism.
The researchers found that brain organoids with only one copy of the CHD8 gene had only two-thirds of the normal level of CHD8 protein in their cells, but that exposure to chlorpyrifos significantly lowered CHD8 levels, turning a moderate deficiency into a severe deficiency. The exposure clearly demonstrated how an environmental factor can exacerbate the effect of a genetic factor, likely worsening disease progression and symptoms.
The researchers also compiled a list of molecules in blood, urine and brain tissue that previous studies have shown to be different in autism spectrum patients.
They found that concentrations of several of these apparent autism biomarkers were also significantly altered in organoids by CHD8 deficiency or chlorpyrifos exposure, and to a greater extent by both.
According to the researchers, the findings pave the way for further studies of gene-environment interactions in disease using human-derived organoids.
Gene–environment interactions in developmental neurotoxicity: a case study of synergy between Chlorpyrifos and CHD8 knockout in human brainspheres
Lena Smirnova
Added on: 07-29-2021
AD patients may benefit from Mediterranean diet
2021
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Alzheimer's Disease (AD) is characterized by a loss of brain volume and an overall cognitive impairment. On the cellular level, ß-amyloid and phosphorylated tau protein (pTau) serve as AD-typical biomarkers. Therapies mostly fail to improve disease progression and the cause remains unclear. To assess if a Mediterranean diet which is characterized by high amounts of fruits, veggies, fish and olive oil but low in red meat and dairy, can contribute positively to the progression, patients with and without (severe) cognitive symptoms were incorporated into the study. The analyses comprised a diet questionnaire, MRT to assess brain volume, determination of AD-related biomarkers in the cerebrospinal fluid and an extensive neuropsychological battery. The results show that following a Mediterranean diet seems to relate to a larger grey matter volume, better memory and less amyloid and pTau.
Mediterranean diet, Alzheimer Disease biomarkers, and brain atrophy in old age
Tommaso Ballarini
Added on: 05-17-2022
COVID-19 can cause severe inflammation in the brain
2021
University Medical Center Freiburg, Freiburg, Germany(1)
University of Freiburg, Freiburg, Germany(2)
University of Freiburg, Freiburg, Germany(2)
The researchers interrogated the brain stem and olfactory bulb in brain samples of COVID-19 patients postmortem using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional single-cell level. They compared this immune map to non-COVID respiratory failure, multiple sclerosis and control patients. The findings show that a severe inflammatory response can develop in the central nervous system of COVID-19 patients involving different immune cells around the vascular system and in the brain tissue. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.
Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T cell interactions
Bertram Bengsch(1), Marco Prinz(2)
Added on: 06-22-2021
Imaging algorithm predicts Alzheimer's onset with 99% accuracy
2021
Vytautas Magnus University, Kaunas, Lithuania
One of the possible Alzheimer’s first signs is mild cognitive impairment (MCI), which is the stage between the expected cognitive decline of normal ageing and dementia. Functional magnetic resonance imaging (fMRI) can be used to identify the regions in the brain which can be associated with the onset of Alzheimer’s disease. The earliest stages of MCI often have almost no clear symptoms, but in quite a few cases can be detected by neuroimaging.
The researchers have developed a deep learning-based method that can predict the possible onset of Alzheimer’s disease from brain images.
For the model, a modification of well-known fine-tuned ResNet 18 (residual neural network) was used to classify functional MRI images obtained from 138 subjects. The images fell into six different categories: from healthy through the spectre of mild cognitive impairment (MCI) to Alzheimer’s disease. In total, 51,443 and 27,310 images from The Alzheimer’s Disease Neuroimaging Initiative fMRI dataset were selected for training and validation.
The model was able to effectively find the MCI features in the given dataset, achieving a classification accuracy of 99% for early MCI vs. AD, late MCI vs. AD, and MCI vs. early MCI, respectively.
Analysis of features of Alzheimer’s Disease: detection of early stage from functional brain changes in magnetic resonance images using a finetuned ResNet18 network
Robertas Damaševičius
Added on: 10-07-2021
Non-invasive investigation of brain states using magnetic resonance imaging
2021
University of Heidelberg, Mannheim, Germany
In this study, network control theory (NCT) was used to investigate transitions between whole-brain neural states measured by functional magnetic resonance imaging (fMRI) during a well-established working memory task. 178 healthy individuals and 24 individuals with schizophrenia were included in the study. Individuals with schizophrenia showed altered network control properties.
Individual prefrontal dopamine receptor expression in each participant was estimated based on genotyping. The hypothesis that the stability of brain states should be related to dopamine receptor function, was tested by functional blocking the receptors using the drugs amisulpride and risperidone in vivo. The obtained data suggest that engagement of working memory involves brain-wide switching between activity states and that the steering of these network dynamics is influenced by dopamine receptor function.
In summary, the utility of NCT for the non-invasive investigation of the mechanistic underpinnings of (altered) brain states and their transitions during cognition was shown.
Brain network dynamics during working memory are modulated by dopamine and diminished in schizophrenia
Urs Braun
Added on: 10-26-2022
Understanding COVID-19-related neurological symptoms
2021
Stanford University School of Medicine, Stanford, USA
SARS-CoV-2 primarily attacks the respiratory system, many COVID-19 patients, however, also show neurological symptoms. Single-nucleus transcriptome analyses from post-mortem frontal cortex and choroid plexus samples across control individuals and patients have revealed interesting discoveries in this study. Gene expression profiles associated with COVID-19 that overlap with those seen in chronic brain disorders could be identified. A molecular framework was established for a better understanding of COVID-19-related neurological symptoms.
Dysregulation of brain and choroid plexus cell types in severe COVID-19
Andreas Keller
Added on: 10-24-2022
Brain-computer interface technique to assist neurorehabilitation
2021
University of Bath, Bath, United Kingdom
Electroencephalography (EEG)-based brain-computer interfaces (BCIs) have been used in the control of robotic arms. The performance of non-invasive BCIs may not be satisfactory due to the poor quality of EEG signals, so shared control strategies were tried as an alternative solution. In this paper, a brain-actuated robotic arm system based on a novel shared control model with a hybrid BCI scheme was proposed. Specifically, a shared controller was built, which dynamically integrated the human intention with machine autonomy and intelligently optimized the robotic arm control process based on the actual control context. The adoption of the hybrid BCI scheme with SI and PI in this study aimed to extend the dimensionality of BCI control and optimize the BCI resources (e.g. decoding computing power, GUI occupation) for the system. The experiment results showed in the current system, all eleven subjects could pick the desired target from
multiple objects under shared control and ten could complete the pick-place task. Moreover, the experiment results also demonstrated that shared control outperformed the pure BCI control, indicating shared control may be a promising method for brain-actuated systems.
This technology could improve the activities of daily living of people with disabilities.
A brain-actuated robotic arm system using noninvasive hybrid brain–computer interface and shared control strategy
Dingguo Zhang
Linfeng Cao et al. Journal of Neural Engineering 2021 [216]
Physicians Committee for Responsible Medicine [217]
Added on: 09-12-2022
Brain-computer interface turns mental handwriting into text
2021
Stanford University School of Medicine, Stanford, USA
Using an implanted sensor to record the brain signals associated with handwriting, scientists have developed a brain-computer interface (BCI) designed to restore the ability to communicate in real-time in people with spinal cord injuries and neurological disorders such as amyotrophic lateral sclerosis (ALS).
By implanting two small sensors on a patient’s brain, researchers were able to decipher the brain activity associated with trying to write letters by hand. A machine-learning algorithm was used to identify letters as the patient attempted to write them, then the system displayed the text on a screen.
Other BCIs for restoring communication exist; however, they have shown to be imprecise and have several limitations. In this study, the participant, whose hand was paralysed from spinal cord injury, achieved typing speeds of 90 characters per minute with 94.1% raw accuracy online, and greater than 99% accuracy offline with a general purpose autocorrect. Researchers hope this technology may one day help restore the ability to communicate with patients with similar problems.
High-performance brain-to-text communication via handwriting
Francis R. Willett
Added on: 07-02-2021
Neurodevelopmental in vitro toxicity assessment
2021
Heinrich-Heine-University, Duesseldorf, Germany
In this study, human-induced pluripotent stem cell (hiPSC)-derived neural crest cells (NCC), mesencephalic cells (LUHMES), 3D human primary neural progenitor cell (NPC)-based neurospheres, as well as hiPSC-derived peripheral neurons were applied to study distinct neurodevelopmental key events. These key events include proliferation, migration, and differentiation of tested cells as well as investigation of cell morphology. The assay battery was tested by evaluating the neurodevelopmental toxicity of several fume retardants. Moreover, RNA sequencing was performed.
This approach represents a case study for a new risk assessment paradigm for neurodevelopmental toxicity by using phenotypic readouts of human cell-based assays that cover a variety of neurodevelopmental key events and studying their molecular signatures in response to different fume retardants. Using a human cell-based neurodevelopmental toxicity assessment (DNT) in vitro battery for hazard assessment is a promising approach for future risk assessment procedures.
Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery
Ellen Fritsche
Added on: 03-17-2022
Recovery of speech in stroke patients predicted by computer simulation
2021
Boston University, Boston, USA(1)
The University of Texas at Austin, Austin, USA(2)
The University of Texas at Austin, Austin, USA(2)
Predicting language therapy outcomes in bilinguals with aphasia (BWA) remains challenging due to the multiple pre-and post-stroke factors that determine the deficits and recovery of their two languages. Computational models that simulate language impairment and treatment outcomes in BWA can help predict therapy response and identify the optimal language for treatment. Here, the BiLex computational model is used to simulate the behavioural profile of language deficits and treatment response of a retrospective sample of 13 Spanish-English BWA who received therapy in one of their languages. Specifically, their pre-stroke naming ability and post-stroke naming impairment in each language were simulated, and their treatment response in the treated and the untreated language. BiLex predicted treatment effects accurately and robustly in the treated language and captured different degrees of cross-language generalization in the untreated language in BWA. A cross-validation approach further demonstrated that BiLex generalizes to predict treatment response for patients whose data were not used in model training. These findings support the potential of BiLex to predict therapy outcomes for BWA and suggest that computational modelling may be helpful to guide individually tailored rehabilitation plans for this population.
Predicting language treatment response in bilingual aphasia using neural network-based patient models
Claudia Peñaloza(1), Uli Grasemann(2)
Added on: 07-01-2021
Skin biopsy allows diagnosis of Parkinson's decades before disease onset
2021
Oregon Health and Science University, Portland, USA
Prodromal Parkinson's disease of the skin, genitourinary, and gastrointestinal systems offers a unique window for understanding early disease pathogenesis and developing disease-modifying treatments. However, prior studies are limited by incomplete timing information, small sample size, and lack of adjustment for known confounders. The researchers aimed to measure onset timing for gastrointestinal, genitourinary, and skin disorders in a large, US-wide clinically characterized cohort of 1.5 million participants. More than 300.000 patients with Parkinson's disease were identified and were compared 4:1 with matched controls. Disorder prevalence and estimated onset times were assessed for 20 years preceding diagnosis. The researchers show that gastrointestinal, genitourinary, and skin disorders manifest decades before the diagnosis of Parkinson's disease, reiterating their potential as sites for developing early diagnostic testing and understanding pathogenesis.
Onset of skin, gut, and genitourinary prodromal Parkinson's disease: a study of 1.5 million veterans
Gregory D. Scott
Added on: 05-12-2022
AI to decode the language of cancer and Alzheimer's disease
2021
University of Cambridge, Cambridge, United Kingdom
Intracellular phase separation of proteins into biomolecular condensates is increasingly recognized as a process with a key role in cellular compartmentalization and regulation. And dysfunction is seen as a trigger for cancer and neurodegenerative diseases such as Alzheimer's disease. To understand how protein sequence determines phase behaviour and to develop an algorithm to predict LLPS-prone sequences(liquid-liquid phase separation), datasets of proteins with different LLPS propensities were created. The DeePhase model showed high performance in both distinguishing LLPS-prone proteins from structured proteins and identifying them within the human proteome. Overall, the results shed light on the physicochemical factors that modulate protein condensation and provide a molecular principles-based platform for predicting protein phase behavior.
Learning the molecular grammar of protein condensates from sequence determinants and embeddings
Tuomas P. J. Knowles
Added on: 04-19-2021
Alzheimer's disease research on brain organoids
2021
Ruhr University Bochum, Bochum, Germany
The amyloid precursor protein (APP) is a type I transmembrane protein with an unknown physiological function but a potential impact on neurodegeneration. The current study demonstrates that APP is involved in nuclear signalling causing the generation of aggregates consisting of its adapter protein FE65, the histone acetyltransferase TIP60 and the tumour suppressor proteins p53 and PML. APP C-terminal (APP-CT50) complexes co-localize and co-precipitate with p53 and PML. The PML nuclear body generation is induced and fusion occurs over time depending on APP signalling and STED (Stimulated Emission Depletion) imaging revealed active gene expression within the complex. It could be shown that the nuclear aggregates of APP-CT50 fragments together with PML and FE65 are present in the aged human brain but not in cerebral organoids differentiated from iPS cells. Notably, human Alzheimer’s disease (AD) brains reveal a highly significant reduction of these nuclear aggregates in areas with high plaque load compared to plaque-free areas of the same individual. Based on these results, it can be concluded that APP-CT50 nuclear signalling takes place in the aged human brain and is involved in the pathophysiology of AD.
Amyloid precursor protein elevates fusion of promyelocytic leukemia nuclear bodies in human hippocampal areas with high plaque load
Thorsten Müller
Added on: 05-12-2021
Blood test for depression and bipolar disorder
2021
Indiana University School of Medicine, Indianapolis, USA
Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently, there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work for everybody. This study took place over four years and included a comprehensive genomic analysis and mood evaluation of over 300 participants. The researchers describe the development of a blood test, composed of 12 RNA biomarkers that can distinguish how severe a patient's depression is, the risk of them developing severe depression in the future, and the risk of future bipolar disorder (manic-depressive illness). The test also provides personalised lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, the study provides objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.
Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs
Alexander B. Niculescu
Added on: 05-11-2021
Brain organoids uncover mechanisms of virus-induced microcephaly
2021
Vienna BioCenter (VBC), Vienna, Austria
Viral infection in early pregnancy is a major cause of microcephaly. However, how distinct viruses impair human brain development remains poorly understood. Here human brain organoids were used to study the mechanisms underlying microcephaly caused by Zika virus (ZIKV) and herpes simplex virus (HSV-1). The authors found that both viruses efficiently replicate in brain organoids and attenuate their growth by causing cell death. However, transcriptional profiling revealed that ZIKV and HSV-1 elicit distinct cellular responses and that HSV-1 uniquely impairs neuroepithelial identity. Furthermore, the authors demonstrated that, although both viruses fail to potently induce the type I interferon (INF) system, the organoid defects caused by their infection can be rescued by distinct type I interferons.
The findings highlighted the distinct paths used by various viruses to cause microcephaly and revealed complex cellular immune defences, such as a neuroprotective role of various type I IFN responses. The importance of these findings also resides in their unique observation in 3D brain organoid cultures, and not in 2D culture systems, thus stressing the superiority of these models in reproducing virus-induced neuropathological conditions and their relevance in studying the mechanisms of viral infections.
Organoid modeling of Zika and herpes simplex virus 1 infections reveals virus-specific responses leading to microcephaly
Jürgen A. Knoblich
Added on: 04-15-2021
Four subtypes of Alzheimer's disease identified by artificial intelligence
2021
Lund University, Lund, Sweden(1)
McGill University, Montréal, USA(2)
McGill University, Montréal, USA(2)
Previously, the pattern of spread of tau pathology in Alzheimer's disease (AD) was thought to be fairly uniform, but recent work has shown considerable variability in the distribution. Here, tau positron emission tomography scans of 1,612 individuals were performed and a computer program and artificial intelligence were used to look for distinctive patterns in the distribution of tau proteins. This revealed that there were four clearly distinguishable patterns for the distribution of tau proteins. The subtypes exhibited different demographic and cognitive profiles and had different longitudinal outcomes. In addition, network diffusion models implied that pathology in the different subtypes originates and propagates through different corticolimbic networks. The results suggest that a reexamination of the term "typical AD" based on a classification of tau pathology would be useful.
Four distinct trajectories of tau deposition identified in Alzheimer’s disease
Oskar Hansson(1), Jacob W. Vogel(2)
Added on: 05-11-2021
In-vitro test for developmental neurotoxicity
2021
University of Veterinary Medicine Hannover, Hannover, Germany
In this study, the pesticide fipronil and its main metabolic product, fipronil sulfone, as well as the known developmental neurotoxicant rotenone were tested on the human neuronal precursor cell line NT2.
The assay tested three developmental neurotoxicity (DNT) endpoints: neurite outgrowth, neuronal differentiation, and precursor cell migration in a dose-dependent manner.
Fipronil and fipronil sulfone were shown to inhibit cell migration and neuronal differentiation and displayed specific developmental neurotoxicity on developing human model neurons.
Developmental neurotoxicity of fipronil and rotenone on a human neuronal in vitro test system
Michael Stern
Added on: 08-08-2022
Three new multiple sclerosis subtypes identified using AI
2021
University College London, London, United Kingdom
Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. To classify MS subtypes based on pathological features, the artificial intelligence tool SuStaIn (Subtype and Stage Inference) was applied to MRI scans of the brain acquired in previously published studies. A training dataset from 6322 MS patients was analysed to define MRI-based subtypes and an independent cohort of 3068 patients was used for validation. Based on the earliest abnormalities, the authors define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. The findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials.
Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data
Arman Eshaghi
Added on: 04-15-2021
3D computer models to study brain mechanics
2021
Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
At FAU in Erlangen, 3D brain computer models have been generated that are composed of small cubes representing the different brain areas. With the help of these models, it is possible to look at the mechanics of individual brain areas. This could be used, for example, to simulate operations, but also to improve disease diagnoses. In the case of many brain diseases such as epilepsy, schizophrenia, Alzheimer's disease and Parkinson's disease, symptoms only become apparent at a very late stage. Thanks to the models, these diseases could be detected earlier. Additionally, this method is used to identify substitute materials for soft tissues, such as hydrogels, which have similar mechanical properties to natural tissues. Thus, it also contributes to the field of tissue engineering, i.e. tissue construction and cultivation.
Silvia Budday
Added on: 03-23-2021
Brain organoids aid drug screening for the Creutzfeldt–Jakob Disease
2021
National Institutes of Health, Hamilton, USA
Creutzfeldt–Jakob Disease (CJD) is a fatal, currently incurable, neurodegenerative disease. The search for candidate treatments would be greatly facilitated by the availability of human cell-based models of prion disease. The authors provide the first evidence that human cerebral organoids can be a viable model for CJD drug screening by using an established anti-prion compound, pentosan polysulfate (PPS). PPS delayed prion propagation in a prophylactic-like treatment paradigm and also alleviated propagation when applied following the establishment of infection in a therapeutic-like treatment paradigm. This study demonstrates the utility of cerebral organoids as the first human 3D cell culture system for screening therapeutic drug candidates for human prion diseases.
Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease
Cathryn L. Haigh
Added on: 06-21-2021
Cloud computing to investigate the link between the visual system and neurodegeneration
2021
Indiana University, Bloomington, USA
The degree to which glaucoma has effects in the brain beyond the eye and the visual pathways is unclear. To clarify this, researchers investigated white matter microstructure (WMM) in 37 tracts of patients with glaucoma, monocular blindness, and controls. Data were collected among the ophthalmologic patient populations of two Universities in Japan and the Netherlands. For analysing the reproducibility, the platform brainlife.io was used. White matter tracts were subdivided into seven categories ranging from those primarily involved in vision (the visual white matter) to those primarily involved in cognition and motor control. In the vision tracts, WMM was decreased as measured by fractional anisotropy in both glaucoma and monocular blind subjects compared to controls, suggesting neurodegeneration due to reduced sensory inputs. A test-retest approach was used to validate these results. The pattern of results was different in monocular blind subjects, where WMM properties increased outside the visual white matter as compared to controls. This pattern of results suggests that whereas in the monocular blind loss of visual input might promote white matter reorganization outside of the early visual system, such reorganization might be reduced or absent in glaucoma. The results provide indirect evidence that in glaucoma unknown factors might limit the reorganization as seen in other patient groups following visual loss.
White matter alterations in glaucoma and monocular blindness difer outside the visual system
Franco Pestilli, Sandra Hanekamp
Added on: 07-01-2021
Human cell-based system reveals potential Alzheimer’s disease mechanism
2021
Massachusetts Institute of Technology (MIT), Cambridge, USA
Apolipoprotein E (APOE) plays an important role in human cells by transporting and metabolizing lipids and assisting energy generation. A variant in the gene encoding APOE, APOE4, increases the risk of Alzheimer’s disease, but how it does this is not well understood.
Here, it was reported, that APOE4, but not APOE3, disrupted the cellular lipidomes of human induced pluripotent stem cell (iPSC)–derived astrocytes generated from fibroblasts of APOE4 or APOE3 carriers, and of yeast expressing human APOE isoforms. The authors combined lipidomics and genome-wide screens in yeast with functional and genetic characterization to demonstrate that human APOE4 induced altered lipid homeostasis. These changes resulted in increased unsaturation of fatty acids and accumulation of intracellular lipid droplets both in yeast and in APOE4-expressing human iPSC-derived astrocytes. The authors then identified the genetic and chemical modulators of this lipid disruption. The study shows that supplementation of the culture medium with choline (a soluble phospholipid precursor) restored the cellular lipidome to its basal state in APOE4-expressing human iPSC-derived astrocytes and in yeast expressing human APOE4. The study illuminates key molecular disruptions in lipid metabolism that may contribute to the disease risk linked to the APOE4 genotype. It is possible that manipulation of lipid metabolism may be a therapeutic approach to alleviate the consequences of carrying the APOE4 allele.
APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
Li-Huei Tsai
Grzegorz Sienski et al. Science Translational Medicine 2021 [240]
Physicians Committee for Responsible Medicine [241]
Added on: 04-15-2021
Linking gestational chemical exposure and autistic behavior in children
2021
Simon Fraser University, Burnaby, Canada
This population study measured the levels of 25 chemicals in blood and urine samples collected from 1,861 Canadian women during the first trimester of pregnancy. A follow-up survey was conducted with 478 of the womens’ children, using Bayesian quantile regression to assess autistic-like behaviours. The researchers found that higher maternal concentrations of cadmium, lead, and some phthalates in blood or urine samples were associated with a higher degree of autistic-like behaviours. Interestingly, the study also indicates which chemicals are negatively associated with autistic-like behaviour in children.
Gestational exposure to toxicants and autistic behaviors using bayesian quantile regression
Joshua D Alampi
Added on: 05-11-2021
Novel method of generating sensation using a brain computer interface
2021
University of Southern California, Los Angeles, USA
Restoring loss of limb function, including sensation, is an important challenge for patients after spinal cord injury, stroke, or limb amputation. In this study, patients already scheduled for surgical implantation for another clinical application had a mini-electrocorticography grid with mECoG bipolar electrodes implanted over the hand area of the primary somatosensory cortex. Then, the area of the brain corresponding to sensations in the hand was systematically stimulated, and the location and description of each sensation were provided by the patient, successfully demonstrating the utility of this novel sensory brain-computer interface (BCI).
Mapping of primary somatosensory cortex of the hand area using a high-density electrocorticography grid for closed-loop brain computer interface
Daniel R. Kramer
Daniel R. Kramer et al. Journal of Neural Engineering 2021 [244]
Physicians Committee for Responsible Medicine [245]
Added on: 07-01-2021
Onset and development of neuroblastoma
2021
German Cancer Research Center (DKFZ), Heidelberg, Germany
Neuroblastoma is a childhood cancer of the developing nervous system. The cellular origin of neuroblastoma has not been defined yet. Single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development have been studied in the present work aiming to identify the cell of origin of neuroblastoma. Using single-cell RNA sequencing, transcriptional similarities between human embryonic adrenal glands and neuroblastoma tumors could be identified. In addition, there was a clear link between the differentiation status of the tumor cell population and its associated clinical phenotype. This significantly improves knowledge of neuroblastoma onset and opens opportunities for therapeutic approaches.
Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma
Frank Westermann
Added on: 10-25-2022
Pain perception in a human model of peripheral nerves
2021
Queen’s University Belfast, Belfast, United Kingdom
Mas-related G-protein-coupled receptor X1 (MrgprX1) is human-specific and its expression is restricted to primary sensory neurons. However, its role in nociception and pain signalling pathways is largely unknown. This study aims to investigate the role of MrgprX1 in nociception via interaction with the pain receptor, Transient Receptor Potential Ankyrin 1 (TRPA1), using in-vitro and in-vivo human neuronal models. Results showed that MrgprX1 activates TRPA1 and induces membrane depolarization in a TRPA1-dependent manner. In addition, MrgprX1 sensitizes TRPA1 to agonist stimulation via Protein Kinase C (PKC). The activation and sensitization of TRPA1 by MrgprX1 in a model of human nerves suggests an important role for this receptor in the modulation of nociception.
Endogenous Mas-related G-protein-coupled receptor X1 activates and sensitizes TRPA1 in a human model of peripheral nerves
Ikhlas El Karim
Added on: 12-02-2022
Blood biomarker discovery for autism spectrum disorder
2021
The Johnson Center for Child Health and Development, Austin, USA
Using machine learning tools to analyse hundreds of proteins, UT Southwestern researchers have identified a group of biomarkers in blood that could lead to an earlier diagnosis of children with autism spectrum disorder (ASD) and, in turn, earlier and more effective therapies.
For the study, serum samples from 76 boys with ASD and 78 from typically developing boys, all ages 18 months to 8 years, were examined.
More than 1,100 proteins were examined using the SomaLogic SOMAScanTM analysis platform. A panel of nine proteins was identified as optimal for predicting ASD using three computational methods. methods. All nine proteins in the biomarker panel were significantly different in boys with ASD compared with typically developing boys and were significantly correlated with ASD severity as measured by ADOS (Autism Diagnostic Observation Schedule) total scores. The researchers evaluated the biomarker panel's quality using machine learning.
Blood biomarker discovery for autism spectrum disorder: A proteomic analysis
Laura Hewitson
Added on: 03-05-2021
Cultivation of 3D brain organoids without Matrigel
2021
UConn School of Medicine, Farmington, USA
Here, the generation of 3D organoid cultures is described, which are generated with a technique called Neurosphere-derived organoid-like aggregates by orbital shaking (NEDAS). This protocol takes advantage of the fusion behavior of neurospheres by generating three-dimensional aggregates without the need for Matrigel like the typical cerebral organoids. NEDAS exhibit proliferation, differentiation and apoptosis with characteristic self-organization. Furthermore, NEDAS have areas with corridors of Neural Progenitor Cells (NPCs) that express markers and features of migratory cells. In addition, the expression of GABAergic and excitatory neurons is shown.
Generation of neurosphere-derived organoid-like-aggregates (NEDAS) from neural stem cells
Jaime Imitola
Added on: 04-18-2023
Human blood-brain-barrier model for repeated dose toxicity testing
2021
University of Artois, Lens, France
The blood-brain barrier (BBB) is a highly restrictive barrier that preserves central nervous system homeostasis and ensures optimal brain function. BBB cell assays can be used to investigate whether an agent can impair the functionality of the BBB and thereby likely lead to neurotoxicity. Recently, several protocols have been published for deriving human brain-like endothelial cells (BLECs) from induced pluripotent stem cells (iPSCs). Here, the question of whether an iPSC-derived model of the BLEC can be used to evaluate the effects of treatment with repeated doses of chemicals was explored, using cyclosporine A (CsA) as a model compound. BLECs were found to retain important properties of the BBB up to 15 days after the end of differentiation and could be used to assess the effects of treatment with repeated doses. Although BLECs still underwent transcriptional changes over time, targeted transcriptome analysis revealed time- and concentration-dependent activation of stress response pathways under CsA treatment. Taken together, these results show that this iPSC model of the BBB and iPSC models, in general, have great potential for investigating the effects of repeated exposure to chemicals and will enable personalised and patient-specific studies in the future.
Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound
Maxime Culot
Added on: 02-15-2022
iPSC-derived microglia for research of Alzheimer's disease
Company 2021
F. Hoffmann-La Roche Ltd., Basel, Switzerland
Microglia are key in the homeostatic well-being of the brain and microglial dysfunction has been implicated in neurodegenerative disorders such as Alzheimer’s disease (AD). Due to the many limitations to study microglia in situ or isolated for large scale drug discovery applications, there is a high need to develop robust and scalable human cellular models of microglia.
Here, the optimization of a protocol to generate microglia from iPSCs in a monoculture condition is presented. The study explores whether these cells can serve as a model to study microglial function and gene expression in the context of TREM2 modulation. TREM2 is a risk gene for AD and an important regulator of microglia. As a major distinction from previously published co-culture methods, in iPSC-generated microglia from monoculture, an increased TREM2 mRNA expression was observed. The regulatory function of TREM2 in these cells was confirmed by comparing wild type with isogenic TREM2 knock-out iPSC microglia. The overall approach resulted in a workstream to generate human iPSC microglia by a directed and neuronal co-culture independent differentiation, resulting in distinct phenotypes for mechanistic studies in AD. This iPSC microglia protocol can now be applied to scale up the production of these cells, study certain AD-related disease settings, and perform compound screening and mechanistic experiments in drug development.
Alzheimer’s risk gene TREM2 determines functional properties of new type of human iPSC-derived microglia
Markus Britschgi, Simon Gutbier
Added on: 05-11-2021
Machine learning identifies candidates for drug repurposing in Alzheimer’s disease
2021
Harvard Medical School, Boston, USA
An artificial intelligence (AI)-based method called DRIAD (Drug Repurposing In Alzheimer’s Disease) is used to screen currently available medications as possible treatments for Alzheimer’s disease. According to the researchers, the method could represent a rapid and inexpensive way to repurpose existing therapies into new treatments for the neurodegenerative condition. It could also help reveal new, unexplored targets for therapy by pointing to mechanisms of drug action.
Machine learning identifies candidates for drug repurposing in Alzheimer’s disease
Artem Sokolov, Mark W. Albers
Added on: 05-11-2021
Regular caffeine consumption affects brain structure
2021
University of Basel, Basel, Switzerland
In this double-blind, randomized, cross-over study, the authors examined the impact of 10-day caffeine on human grey matter volumes by fMRI in 20 habitual caffeine consumers, compared with 10-day placebo. A significant reduction in grey matter volume in the medial temporal lobe was detected after 10 days of caffeine intake compared with 10 days of placebo. However, the data do not suggest a link between sleep depth during daily caffeine intake and changes in brain morphology. In conclusion, daily caffeine intake might induce neural plasticity depending on individual metabolic processes.
Daily caffeine intake induces concentration-dependent medial temporal plasticity in humans: a multimodal double-blind randomized controlled trial
Christian Cajochen
Added on: 05-11-2021
Influence of toxic metals on neurodegenerative diseases
2021
University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia
The aim of this study was to investigate the influence of toxic metals present in the environment on the molecular mechanisms involved in the development of the neurodegenerative diseases (ND) amyotrophic lateral sclerosis (ALS), Parkinson’s Disease (PD) and Alzheimer’s disease (AD). Moreover, it investigated the capability of in silico toxicogenomic data-mining for distinguishing the probable mechanisms of mixture-induced toxic effects. The linkage between neurodegenerative diseases and toxic metals (Pb, MeHg (neurotoxic, organic form of mercury), Cd, As) was explored by analysing the chemical–gene/protein interactions obtained from the Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org). The CTD data mining analysis revealed the genes connected to each of the investigated metals and linked to the development of the selected neurodegenerative diseases.
SOD2 gene was noted as the mutual gene for all the selected ND. Oxidative stress, folate metabolism, vitamin B12, and apoptosis were noted as the key disrupted molecular pathways that contribute to the neurodegenerative disease’s development. The results emphasize the role of oxidative stress, particularly SOD2, in neurodegeneration triggered by environmental toxic metal mixture and give a new insight into common molecular mechanisms involved in ALS, PD and AD pathology.
Elucidating the influence of environmentally relevant toxic metal mixture on molecular mechanisms involved in the development of neurodegenerative diseases: In silico toxicogenomic data-mining
Danijela Đukić-Ćosić
Added on: 02-05-2024
Model of the gut-liver-brain axis for studying neurodegenerative diseases
2021
Massachusetts Institute of Technology, Cambridge, USA(1)
Whitehead Institute for Biomedical Research, Cambridge, USA(2)
Whitehead Institute for Biomedical Research, Cambridge, USA(2)
In the study of neurodegenerative diseases (NDs), there is an urgent need for highly controlled in vitro systems to investigate organ-organ– and organ-immune–specific interactions relevant for disease pathophysiology. Of particular interest is the gut/microbiome-liver-brain axis for parsing out how genetic and environmental factors contribute to NDs. Here a mesofluidic platform technology to study gut-liver-cerebral interactions in the context of Parkinson’s disease (PD) was developed. It connects microphysiological systems (MPSs) of the primary human gut and liver with a human induced pluripotent stem cell-derived cerebral MPS in a systemically circulated common culture medium containing CD4+ regulatory T and T helper 17 cells. A patient-derived cerebral MPS carrying the PD-causing A53T mutation was used as an application example. Herein, the authors demonstrated that systemic interaction enhances features of in vivo–like behaviour of cerebral MPS, and that microbiome-associated short-chain fatty acids increase expression of pathology-associated pathways in PD.
Human physiomimetic model integrating microphysiological systems ofthe gut, liver, and brain for studies of neurodegenerative diseases
Linda G. Griffith (1), Rudolf Jaenisch(2)
Martin Trapecar et al. 2021 Science Advances [258]
Physicians Committee for Responsible Medicine [259]
Added on: 05-10-2021
Risky behaviour through genetic and neuroanatomic dispositions
2021
University of Pennsylvania, Philadelphia, USA
Brain scans of 25,000 people were used to investigate the basis and mechanisms of risky behaviours (drinking, smoking, driving and sexual behaviour) by determining the correlation of genetic and neuroanatomical traits. Certain genetic dispositions promote risky behaviour; moreover, functional and anatomical differences were found in the brains of risk-taking subjects. These could also be discovered in the cerebellum, which was previously thought to be predominantly responsible for fine motor skills but seems to play a role also in decision-making processes.
Genetic underpinnings of risky behaviour relate to altered neuroanatomy
Gideon Nave
Added on: 02-04-2021
A prognostic Alzheimer’s disease blood test in the symptom-free stage
December 2020
Ruhr University Bochum, Bochum, Germany
The authors evaluated amyloid-beta misfolding as a prognostic tool for future clinical progression to mild cognitive impairment or dementia due to Alzheimer’s disease (AD) in 203 individuals with subjective cognitive decline over the course of 6 years. The results suggest that a panel of structure- and concentration-based plasma amyloid biomarkers may predict conversion to clinical mild cognitive impairment and dementia due to AD in cognitively unimpaired subjects. These plasma biomarkers provide a noninvasive and cost-effective alternative for screening early AD pathological changes.
Amyloid-β misfolding as a plasma biomarker indicates risk for future clinical Alzheimer’s disease in individuals with subjective cognitive decline
Klaus Gerwert
Added on: 01-29-2021
Brain organoids used to identify promising treatments for Rett syndrome
December 2020
University of California San Diego, La Jolla, USA
The gene mutation that causes Rett syndrome, a form of autism spectrum disorders (ASD), was discovered decades ago, but progress on treating it has lagged, at least in part because mouse model studies have not translated to humans. This study is therefore concerned with finding a model that better mimics the human brain. The researchers generated brain organoids using induced pluripotent stem cells (iPSCs) derived from patients with Rett syndrome, which preserve each patient’s unique genetic background, to study the disease and screen for potential treatments. They treated the brain organoids with 14 drug candidates that are known to affect various brain cell functions in an attempt to identify suitable therapies. Two of the substances could reverse the disease symptoms in the brain organoids to ‘near-normal’.
Pharmacological reversal of synaptic and network pathology in human MECP2-KO neurons and cortical organoids
Alysson R Muotri, Cleber A Trujillo
Added on: 06-21-2021
Human in vitro neurotoxicity assay with LUHMES cells
December 2020
University of Konstanz, Konstanz, Germany
A highly reproducible in vitro neurotoxicity assay using human cells is presented, allowing assessment of complex signalling in both individual human neurons and on the network level. As test system basis, LUHMES cells were used, which are well established for morphological, metabolical and biochemical neurotoxicity testing. The authors established Ca2+-signalling as the main endpoint, on the population level, as well as on the level of individual cells and confirmed their basic neuroexcitability parameters. To exemplify potential studies on ion channels, voltage-gated sodium channels and their inhibition by tetrodotoxin, saxitoxin and lidocaine, as well as their opening by the plant alkaloid veratridine and the food-relevant marine biotoxin ciguatoxin were characterized. In addition, oscillations of [Ca2+]i across the entire culture dish were identified and exemplified as a readout for neuronal connectivity and as a measure to identify compounds modifying neuronal network features.
Human neuronal signaling and communication assays to assess functional neurotoxicity
Marcel Leist
Added on: 03-23-2021
iPSC-derived neuronal cultures to study SARS-CoV-2 neurotropism
December 2020
Beckman Research Institute of City of Hope, Duarte, USA(1)
University of California, Los Angeles, USA(2)
University of California, Los Angeles, USA(2)
In vitro models are critical for understanding the mechanism of diseases. Using the hiPSC differentiation technology, neurons, astrocytes and brain organoids were generated to study neurotropism and the cellular response to SARS-CoV-2. While the viral infection of hiPSC-derived neurons and astrocytes was low, a boosted infection in neuron-astrocyte co-cultures and organoids was observed. ApoE4/4 hiPSCs-derived neurons and astrocytes had an increased rate of SARS-CoV-2 infection. ApoE4, a strong genetic risk factor for Alzheimer's disease, has been associated with an increased risk for severe COVID-19. Remdesivir treatment inhibited SARS-CoV2 infection of hiPSC neurons and astrocytes. The findings from the present study reveal the potential role of ApoE4 in COVID-19 severity. They give also insight into the impact of COVID-19 on different patient populations.
ApoE-isoform-dependent SARS-CoV-2 neurotropism and cellular response
Yanhong Shi(1), Vaithilingaraja Arumugaswami(2)
Added on: 10-24-2022
Optimization of neuronal cell cultures using a microfluidic device
December 2020
University of Luxembourg, Luxembourg, Luxembourg
Using a newly designed microfluidic device for neuron cell cultures, it was possible to circulate liquid media continuously over 24 hours. The biological compatibility of the "OrganoPlate" was demonstrated with the differentiation of human neuroepithelial stem cells into dopaminergic neurons. This system can provide further insights into research into Parkinson's disease, among other things.
Passive controlled flow for Parkinson's disease neuronal cell culture in 3D microfluidic devices
Jens C. Schwamborn
Added on: 10-15-2020
AI for detecting cerebral aneurysms with CT angiography
November 2020
Huazhong University of Science and Technology, Wuhan, China
A highly sensitive deep learning-based algorithm for automated detection of cerebral aneurysms on CT angiography images was introduced. A total of 1068 CT angiograms were evaluated used for the training and the validation set. The sensitivity of the proposed algorithm for detecting cerebral aneurysms was 97.5%. Moreover, eight new aneurysms that had been overlooked in the initial reports were detected. Using this algorithm radiologists’ performance in detecting aneurysms improved, especially for less experienced radiologists.
Deep learning for detecting cerebral aneurysms with CT angiography
Xi Long
Added on: 11-12-2020
AI predicts schizophrenia symptoms in at-risk population
November 2020
National Institute of Mental Health and Neuro Sciences, Bangalore, India(1)
University of Alberta, Edmonton, Canada(2)
University of Alberta, Edmonton, Canada(2)
First-degree relatives of schizophrenia patients have up to a 19 per cent risk of developing schizophrenia during their lifetime, compared with the general population risk of less than one per cent. The tool EMPaSchiz (Ensemble algorithm with Multiple Parcellations for Schizophrenia prediction) can predict a diagnosis of schizophrenia with 87 per cent accuracy by examining patient brain scans. Functional magnetic resonance images of 57 healthy first-degree relatives (siblings or children) of schizophrenia patients were analyzed. The method accurately identified the 14 individuals who scored highest on a self-reported schizotypal personality trait scale.
The next step is to test the accuracy of the tool on nonfamilial individuals with schizotypal traits and to track assessed individuals over time to learn whether they develop schizophrenia later in life.
Extending schizophrenia diagnostic model to predict schizotypy in first-degree relatives
Ganesan Venkatasubramanian(1), Sunil Vasu Kalmady(2)
Added on: 02-11-2021
Breakthrough organoid technology finds microcephaly genes in the human brain
November 2020
Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna, Austria
Loss-of-function (LOF) screens provide a powerful approach to identify regulators in biological processes. The study presents a method called CRISPR-LIneage tracing at Cellular resolution in Heterogenous Tissue (CRISPR-LICHT), enabling parallel LOF studies in human cerebral organoid tissue. The method was used to test 173 microcephaly candidate genes revealing 25 to be involved in known and uncharacterized microcephaly-associated pathways. This human tissue screening technology allows the identification of microcephaly genes and mechanisms involved in brain size control.
A human tissue screen identifies a regulator of ER secretion as a brain size determinant
Jürgen A. Knoblich
Added on: 11-06-2020
Fluorescent brain organoids for the study of function and disease
November 2020
Ruhr University Bochum, Bochum, Germany
Cerebral organoids are a promising model to study human brain function and disease, but the high variability between organoids presents a challenge. A method using labelled mixed organoids generated from two different human iPSC (hiPSC) lines is presented. This allows the identification of cells of different origins within a single organoid and overcomes the limitations of inhomogeneity between organoids. Using a CRISPR/Cas9 gene-editing approach, different fluorescent proteins were fused to β-actin or lamin B1 in hiPSCs and subsequently used as markers to identify each cell line. Mixtures of differentially edited cells were seeded to induce embryoid body formation and cerebral organoid differentiation. Subsequently, 3D tissue development could be followed by confocal fluorescence microscopy and immunofluorescence staining in fixed samples. Overall, the results support the possibility of using differentially labelled reporter cell lines with different characteristics (e.g., mutation-containing and "healthy cells") to generate more accurate human models that allow direct comparison under identical experimental conditions.
Gene edited fluorescent cerebral organoids to study human brain function and disease
Thorsten Müller
Added on: 05-12-2021
How SARS-CoV-2 reaches the brain
November 2020
Charité–Universitätsmedizin Berlin, Berlin, Germany
Using post-mortem tissue samples, the researchers have studied the mechanisms by which SARS-CoV-2 can reach the brains of patients with COVID-19, and how the immune system responds to the virus once it does. The results show that SARS-CoV-2 enters the brain via nerve cells in the olfactory mucosa. SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control centre in the medulla oblongata.
Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19
Frank L. Heppner
Added on: 12-18-2020
Human model for neuronal development and disorders
November 2020
Charité-Universitätsmedizin, Berlin, Germany(1)
University of Konstanz, Konstanz, Germany(2)
University of Konstanz, Konstanz, Germany(2)
Disturbances during fetal development lead to congenital malformations (spina bifida, anencephaly) and may contribute to neuropsychiatric disorders like attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) or schizophrenia.
This human embryonic stem cell (hESC)-model is suitable to study the early development of the neuroectodermal layer and later nervous system. It allows the analysis of the highly dynamic and large-scale transcriptome changes which occur during (normal) neurodevelopment. Moreover, by introducing the neurotoxic valproic acid, clinically relevant neurodevelopmental disorder models can be established. Yet little is known about the underlying mechanisms and this model may contribute to study disease mechanisms within a broadly applicable field.
Kinetic modeling of stem cell transcriptome dynamics to identify regulatory modules of normal and disturbed neuroectodermal differentiation
Nils Blüthgen(1), Marcel Leist(2)
Added on: 04-27-2021
Lung and brain organoids for COVID-19 research
November 2020
Centre for Comparative Medicine and Bioimage of Catalonia (CMCiB), Barcelona, Spain
Researchers at the Centre for Comparative Medicine and Bioimage of Catalonia (CMCiB) will infect human lung and brain organoids with SARS-CoV-2 directly obtained from patients. The final objective is to study how this virus affects human organs and the effectiveness of various drugs at halting the infection. This is possible thanks to the use of artificial intelligence (AI), that can detect to what degree the organoids are affected by the infection and the role of the drugs in each case.
The first projects on SARS-CoV-2 in lab-designed mini human organs gets underway
Pere-Joan Cardona
Added on: 11-23-2020
More education may not protect against dementia
November 2020
Karolinska Institutet, Stockholm, Sweden
The researchers compared the different educational lengths with dementia diagnoses of 1.3 million Swedish people born between 1920 and 1936. Analyses indicated very small or negligible causal effects of education on dementia risk. These findings suggest that education alone cannot be uncritically considered as a modifiable risk factor for dementia.
Does prolonged education causally affect dementia risk when adult socioeconomic status is not altered? A Swedish natural experiment on 1.3 million individuals
Dominika Seblova
Added on: 12-18-2020
Novel tau biomarkers for presymptomatic Alzheimer’s disease
November 2020
Barcelonaβeta Brain Research Center (BBRC), Barcelona, Spain(1)
University of Gothenburg, Gothenburg, Sweden(2)
University of Gothenburg, Gothenburg, Sweden(2)
The researchers have found three new forms of the tau protein that become abnormal in the very early stages of Alzheimer's disease before cognitive problems develop and can be thus used as diagnostic biomarkers. The scientists developed new tools to detect these subtle changes and confirmed their results in two studies with 381 and 503 human participants, respectively. The findings are also important for the testing of therapies against Alzheimer's disease.
Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer’s continuum when only subtle changes in Aβ pathology are detected
José Luis Molinuevo(1), Kaj Blennow(2)
Marc Suárez‐Calvet et al. EMBO Molecular Medicine 2020 [281]
Bionity [282]
Thomas K. Karikari et al. Alzheimer's & Dementia 2020 [283]
Added on: 01-29-2021
Train AI to adapt like human brains
November 2020
Salk Institute for Biological Studies, La Jolla, USA
The prefrontal cortex (PFC) enables humans’ ability to flexibly adapt to new environments and circumstances. Disruption of this ability is often a hallmark of prefrontal disease. Neural network models have provided tools to study how the PFC stores and uses information, yet the mechanisms underlying how the PFC is able to adapt and learn about new situations without disrupting preexisting knowledge remain unknown. Here a neural network architecture called DynaMoE is used to show how hierarchical gating can naturally support adaptive learning while preserving memories from prior experience. Furthermore, the authors show how damage to the network model recapitulates disorders of the human PFC.
A modeling framework for adaptive lifelong learning with transfer and savings through gating in the prefrontal cortex
Ben Tsuda, Terrence J. Sejnowski
Added on: 12-21-2020
Artificial intelligence helps in the search for biomarkers for Alzheimer's
October 2020
University of Pennsylvania School of Medicine, Philadelphia, USA
Researchers of 12 research centers will collaborate to determine more precise diagnostic biomarkers and drug targets for Alzheimer´s disease. For the project, the teams will apply advanced artificial intelligence (AI) methods to integrate and find patterns in genetic, imaging, and clinical data from over 60,000 Alzheimer's patients. The project's first objective will be to find a relationship between the three modalities (genes, imaging, and clinical symptoms), in order to identify the patterns that predict Alzheimer's diagnosis and progression -- and to distinguish between several subtypes of the disease.
The investigators will then use those findings to build a predictive model of cognitive decline and Alzheimer's disease progression, which can be used to steer treatment for future patients.
Using advanced AI to discover diagnostic biomarkers and drug targets for Alzheimer’s
Christos Davatzikos
Added on: 11-12-2020
Microbiota transfer therapy in autistic children
October 2020
Arizona State University, Tempe, USA
Fecal microbiota transplant (FMT) is a promising therapy to repair dysbiotic gut microbiota. The authors previously performed intensive FMT called microbiota transfer therapy (MTT) for children with autism spectrum disorders and observed a substantial improvement of gastrointestinal and behavioural symptoms. This study presents comprehensive metabolite profiles from plasma and fecal samples of the children who participated in the MTT trial. With 619 plasma metabolites detected, the authors found that the autism group had distinctive metabolic profiles at baseline. In contrast, for 669 fecal metabolites detected, when correcting for multiple hypotheses, no metabolite was significantly different at baseline. MTT had a systemic effect, resulting in substantial changes in plasma metabolites, driving a number of metabolites to be more similar to those from typically developing children.
Distinct fecal and plasma metabolites in children with autism spectrum disorders and their modulation after microbiota transfer therapy
Rosa Krajmalnik-Brown, Dae-Wook Kang
Added on: 11-23-2020
SARS-CoV-2 infects and disrupts the choroid plexus in human brain organoids
October 2020
Cambridge Biomedical Campus, Cambridge, United Kingdom
Coronavirus disease caused by SARS-CoV-2 leads to respiratory pathologies that range from non-symptomatic infections to fatal cases. Additionally, there have been reports of neurological symptoms, but the mechanisms behind these complications remain unknown. Here, human pluripotent stem cells were used to generate brain organoids to study SARS-CoV-2 neurotropism and uncover potential mechanisms underlying the neural pathology associated with the disease. The results showed that ACE2 viral receptor was expressed in choroid plexus epithelial cells but not in other brain cell types, which refers to the infection of only epithelial choroid plexus epithelial cells with the live virus or spike pseudovirus. Furthermore, the infection affected a subtype of more mature cells expressing apolipoprotein and ACE2. Finally, choroid plexus infection drove damages in the epithelium and barrier leakage. Overall, the researchers demonstrate that there are brain cells susceptive to being infected by SARS-CoV-2 and, when these cells are damaged, lead to choroid plexus disruption and barrier leaking.
SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids
Madeline A. Lancaster
Added on: 11-29-2021
State-of-the-art AI methods used to study Alzheimer’s
October 2020
USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, USA
In the National Institutes of Health-funded initiative "Ultrascale Machine Learning to Empower Discovery in Alzheimer's Disease Biobanks" (AI4AD), 11 research centres have joined forces to use artificial intelligence and machine learning to support Alzheimer's research into causes and treatments. Experts from computer science, genetics, neurosciences and imaging sciences are involved.
The project's first objective is to identify genetic and biological markers that predict Alzheimer's diagnosis and distinguish between several subtypes of the disease. To accomplish this, the research team will apply sophisticated AI and machine learning methods to a variety of data types, including tens of thousands of brain images and whole-genome sequences. The investigators will then relate these findings to the clinical progression of Alzheimer's, including in patients who have not yet developed dementia symptoms. The AI methods will be trained on large databases of brain scans to identify patterns that can help detect the disease as it emerges in individual patients.
State-of-the-art AI methods used to study Alzheimer’s
Paul Thompson
Added on: 11-19-2020
A novel skin biomarker for Parkinson disease
2020
Case Western Reserve University School of Medicine, Cleveland, USA
One important question is whether the pathological α-synuclein (αSynP) detected by immunohistochemistry in the skin of individuals with Parkinson's disease (PD) has aggregation seeding activity, and is skin αSynP seeding activity a potential biomarker for diagnosis of PD and other synucleinopathies. In this diagnostic study including skin samples from 160 autopsies and 41 biopsies, a statistically significant increase in αSynP seeding activity was observed in individuals with PD and synucleinopathies compared with controls with tauopathies and non-neurodegenerative diseases. This study provides a proof-of-concept that skin αSynP seeding activity may serve as a novel biomarker for antemortem diagnoses of PD and other synucleinopathies.
Skin α-synuclein aggregation seeding activity as a novel biomarker for Parkinson disease
Shu G. Chen, Wen-Quan Zou
Added on: 05-12-2022
Brain organoids for HIV research
2020
University of Pittsburgh, Pittsburgh, USA
The infection with HIV-1 can result in HIV-associated neurocognitive disorder (HAND), which is characterized by neuroinflammation and neurodegeneration and results in cognitive impairment of affected patients. The aim of this study was to develop a brain-representative in-vitro system to investigate the molecular events underlying HIV neuropathogenesis.
Therefore, a three-dimensional (3D) human brain organoid (hBORG) model containing major cell types important for HIV-1 neuropathogenesis; in particular neurons and astrocytes, was developed. The ability of these hBORGs to support HIV-1 infection as well as to recapitulate the hallmarks of central nervous system (CNS) pathology seen in HIV-1 patients was investigated by incorporating HIV-infected primary microglia. Incorporation of HIV-infected microglia resulted in inflammatory response and induced damage to neurons and astrocytes, which represents major hallmark features seen in the CNS of HIV-1 infected individuals.
This model offers great promise for basic understanding of how HIV-1 infection alters the CNS and induces pathological changes, paving the way for discovery of biomarkers and new therapeutic targets.
Modeling HIV‑1 neuropathogenesis using three‑dimensional human brain organoids (hBORGs) with HIV‑1 infected microglia
Velpandi Ayyavoo, Shilpa Sant
Added on: 04-03-2023
Long-lasting and broad effects of nutritional intervention in early Alzheimer’s
2020
University of Eastern Finland, Kuopio, Finland
If patients with early-stage Alzheimer’s disease are given a medical nutrition drink containing a multinutrient formulation, the impact of the disease can be slowed. Trial participants who received a multinutrient formulation over an extended period of time showed a significantly less rapid deterioration in cognitive performance than the patients in a control group, who received only a placebo. These findings are from an ongoing European study LipiDiDiet in which 311 patients in eleven hospitals have been monitored for three years.
36‐month LipiDiDiet multinutrient clinical trial in prodromal Alzheimer's disease
Hilkka Soininen
Added on: 11-23-2020
Patient-derived cells and brain organoids uncover treatment targets in Parkinson’s disease
2020
University of Luxembourg, Luxembourg, Luxembourg
Mutations in PARK7 lead to the development of early-onset Parkinson’s disease (PD). The authors of this study identified an exonic splicing mutation in PARK7 linked to PD and studied the effect of this mutation in patient-derived cellular models. The mutation resulted in impaired splicing, reduced production of DJ-1 protein, and consequent mitochondrial dysfunction. Using precise bioinformatics algorithms, the researchers performed an automated drug screen and identified a combination of two substances that rescued the aberrant splicing and neuronal loss in patient-derived brain organoids. The results suggest that precision medicine targeting specific molecular signatures could be an effective strategy for PD and possibly other neurodegenerative diseases.
A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease
Rejko Krüger
Added on: 09-25-2020
Brain areas decoding acoustic and visual communication cues
2020
University of Dundee, Dundee, United Kingdom
Visual speech through lip movements is a key component of communication, but the brain mechanisms that process these visual and auditory cues are still unclear. Here, a multifactorial whole-brain magnetoencephalography (MEG) classification of volunteers was used to identify brain areas activated during different tests of auditory and visual communication. The results showed which areas processed auditory and visual mediated word identities. However, only two brain areas were identified that were activated along with auditory and visual cues and were clearly separated from other areas that represented sensory-mediated word identity. Overall, the researchers elucidate which brain areas are activated by two different types of communication and suggest that word comprehension may be more specific to communication channels than is currently thought.
Shared and modality-specific brain regions that mediate auditory and visual word comprehension
Anne Keitel
Added on: 11-30-2021
Combination of machine learning and brain imaging create better diagnostics for mental illness
2020
Hamamutsu University School of Medicine, Hamamatsu City, Japan(1)
The University of Tokyo, Tokyo, Japan(2)
The University of Tokyo, Tokyo, Japan(2)
A computer algorithm was trained on MRI brain scans (magnetic resonance imaging) of 206 autism, schizophrenia and psychosis patients as well as people with no mental health concerns. A total of six different algorithms were used to discriminate between the different MRI images of the patient groups. This allowed associating different psychiatric diagnoses with variations in the thickness, surface or volume of areas of the brain on the MRI images. After a training period, the algorithm was tested with brain scans of another 43 patients. The machine's diagnosis matched the psychiatrists' assessments with high reliability and up to 85 per cent accuracy.
Machine-learning classification using neuroimaging data in schizophrenia, autism, ultra-high risk and first-episode psychosis
Hidenori Yamasue(1), Shinsuke Koike(2)
Added on: 09-22-2020
Functional NMJ system for personalized ALS modeling and drug testing
2020
University of Central Florida, Orlando, USA
Loss of the neuromuscular junction (NMJ) is an early and critical hallmark in all forms of amyotrophic lateral sclerosis (ALS). An ALS-NMJ system is established by using motor neuron stem cells from ALS patients and integrating them into a chambered system. Myotube contractions are recorded while MNs are stimulated by field electrodes and a set of clinically relevant parameters are defined to characterize NMJ function. The utilization of three ALS mutant lines revealed significant NMJ deficits in all mutant lines, but variations in severity and parameter selection, as well as in response to drug treatment, highlight the need for patient-specific models.
A human‐based functional NMJ system for personalized ALS modeling and drug testing
James J. Hickman
Added on: 09-24-2020
iPSC-derived ALS muscle model to study muscle pathology
2020
University of Central Florida, Orlando, USA
This study aimed to investigate the regenerative and functional deficits of the ALS (Amyotrophic lateral sclerosis) skeletal muscle by developing a functional in vitro phenotypic skeletal muscle model from ALS patient-derived iPSCs (ALS-iPSCs) harbouring mutations in the SOD1 gene. This patient iPSC-derived muscle model is free of other cell types such as motoneurons and allows the investigation of muscle pathology from myogenesis to functional muscle formation. With the iPSC-derived model, the authors demonstrated that ALS-iPSC myoblasts have deficits in fusion despite their expression of appropriate myogenic markers. Additionally, significant morphological and structural alterations were identified in iPSC-derived ALS myotubes that correlated with decreased contractile and metabolic function. Furthermore, a subcellular investigation revealed that ALS skeletal muscle had altered mitochondrial function, which may negatively impact metabolic pathways and energy generation. Compared to previous iPSC-derived muscle studies, this investigation provides a detailed and comprehensive view of the morphological and structural deformity of ALS muscle and demonstrates for the first time their functional defects in contractibility, as well as their metabolic dysregulation. The abnormalities revealed in these patient iPSC derived muscle models indicates that endogenous expression of the mutant SOD1 gene in muscle, independent of the influence of motoneurons, has a toxic effect on skeletal muscle regeneration and function, which supports the active role of muscle in neuromuscular junction degradation and ALS onset and/or progression. The results indicate that this model may provide a human-relevant platform for ALS research and drug development studies.
Functional skeletal muscle model derived from SOD1‑mutant ALS patient iPSCs recapitulates hallmarks of disease progression
James J. Hickman
Added on: 04-15-2021
A prognostic model for overall survival in sporadic Creutzfeldt‐Jakob disease
2020
University of Münster, Münster, Germany
The authors developed the first prognostic model for overall survival of Creutzfeldt‐Jakob disease patients based only on readily available information from 1226 patients. The model integrates patients’ age, sex, codon 129 genotype, and specific biomarker in the cerebrospinal fluid (CSF tau data). The developed score chart serves as a hands‐on prediction tool for clinical practice.
A prognostic model for overall survival in sporadic Creutzfeldt‐Jakob disease
Nicole Rübsamen
Franc Llorens et al. Alzheimer's & Dementia: The Journal of the Alzheimer's Associatio [304]
Bionity [305]
Added on: 07-22-2020
Neuronal organoids mimicking network activity of fetal brain
2020
Georg-August-University, Goettingen, Germany
In this study, the directed self-organization of human induced pluripotent stem cells towards a highly interconnected neuronal network is reported. The described bioengineered neuronal organoids (BENOs) consist of functionally integrated excitatory and inhibitory neurons as well as supporting glia. Giant depolarizing potential (GDP)-like events observed in early BENO cultures mimic early network activity of the fetal brain. The observed reduction of GDPs in > 40-day BENOs indicates progressive neuronal network maturation.
Collectively, BENOs demonstrate neuronal network function classically found in the developing brain, such as GDP, and within the more matured human brain, such as neuronal plasticity. The similarity of structural and functional properties to the fetal brain may allow for the application of BENOs in studies of neuronal plasticity and modelling of diseases as well as in drug development.
Developmental GABA polarity switch and neuronal plasticity in bioengineered neuronal organoids
Wolfram-Hubertus Zimmermann, Maria-Patapia Zafeiriou
Added on: 08-24-2022
3D organoid made of human cells to model the blood-brain barrier and screen drugs
2020
Wake Forest School of Medicine, Winston-Salem, USA
The blood-brain barrier (BBB) comprises a complex arrangement of various cell types which constitute a physical and enzymatic barrier between the brain and the bloodstream. BBB is essential for maintaining the brain's homeostasis. During ischemic stroke, BBB breakdown leads to oedema and haemorrhage which cause major brain damage. The lack of an agreed ischemic stroke model limits the search for molecular therapies. In the present study, the researchers aimed at developing a six cell-type neurovascular unit human organoid model for use in neurotoxicity screening and disease modelling. Human brain microvascular endothelial cells, pericytes, astrocytes, oligodendrocytes, microglia and neurons were obtained from primary material or differentiated from induced pluripotent stem cells. The six cell types were assembled into a 3D organoid in vitro that was then cultured in hypoxia conditions to mimic stroke. The researchers measured changes in expression levels of proteins critical in BBB maintenance/function. The secretion and effect of inflammatory mediators were also assessed. The changes due to hypoxia could be lowered using drugs known to act on hypoxia stress and inflammation, hence validating the model. The study concludes that such neurovascular spheroid is a suitable model for mimicking cerebral pathology, such as hypoxia, that will allow for in vitro testing and the development of novel therapies for diseases of the central nervous system.
Multicellular 3D neurovascular unit model for assessing hypoxia and neuroinflammation induced blood-brain barrier dysfunction
Goodwell Nzou
Added on: 12-20-2021
Human CNS barrier-forming organoids with cerebrospinal fluid production
2020
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
The cerebrospinal fluid (CSF) is a vital fluid that provides nutrients and signalling molecules and removes toxic by-products from the brain. CSF is produced by the choroid plexus (ChP), a protective epithelial barrier that also prevents the free entry of blood. Here, human ChP organoids were established with a selective barrier and CSF-like fluid secretion in self-contained compartments. This in vitro barrier has been shown to have the same small molecule selectivity as in vivo, and ChP-CSF organoids can predict CNS permeability of novel compounds. The transcriptomic and proteomic signature of ChP-CSF organoids showed a high degree of similarity to in vivo. Finally, overlap of single-cell transcriptomics and proteomic analysis revealed important human CSF components produced by previously unidentified specialized epithelial subtypes.
Human CNS barrier-forming organoids with cerebrospinal fluid production
Madeline A. Lancaster
Added on: 05-11-2023
MRI shows brain iron accumulation in Alzheimer's patients
2020
Medical University of Graz, Graz, Austria
The authors developed a modified MRI approach to analyze the iron content in the neocortex of Alzheimer’s disease (AD) patients. The brains of 100 AD patients and 100 healthy volunteers were examined with a follow-up analysis after 17 months. Iron concentration in the deep grey matter and neocortical regions was higher in AD patients than in healthy control participants. Changes in iron levels over time in the temporal lobe were associated with cognitive decline in individuals with AD.
Cross-sectional and longitudinal assessment of brain iron level in Alzheimer disease using 3-T MRI
Reinhold Schmidt
Added on: 09-17-2020
Neurobiology of COVID-19
2020
Johns Hopkins Medicine, Baltimore, USA
Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in COVID-19 patients. The authors review the reports that address neurological manifestations in patients with COVID-19 even without typical respiratory symptoms such as fever, cough, or shortness of breath. Furthermore, they discuss the different neurobiological processes and mechanisms that may be involved and propose a basic “NeuroCovid” classification scheme to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.
Neurobiology of COVID-19
Majid Fotuhi
Added on: 06-26-2020
Neurotoxicity assay for the evaluation of marine biotoxins
2020
University of Konstanz, Konstanz, Germany
A microcystin assay was developed for human neurotoxicity caused by marine biotoxins. Using the data for preliminary risk assessment showed that normal ambient/environmental exposure levels are unlikely to trigger neurotoxicity, whereas higher concentrations result in reduction in cell count or neurite area.
The cells used in this assay are LUHMES (Lund human mesencephalic) as well as human peripheral neurons derived from pluripotent stem cells.
Examination of microcystin neurotoxicity using central and peripheral human neurons
Marcel Leist
Added on: 07-22-2020
New method shows chemical interaction in Parkinson's disease
2020
Chalmers University of Technology, Gothenburg, Sweden
The interaction of the neuronal protein α-synuclein with lipid membranes appears crucial in the context of Parkinson’s disease. However, the underlying mechanisms are not yet identified. Single-vesicle resolution fluorescence and label-free scattering microscopy in combination provide the advantage to measure the tiniest amounts of molecules and their reactions. The combined methods have now shown that the human α-synuclein interacts differently with different types of lipid vesicles. It disrupts the mitochondrial-like vesicles, indicating that mitochondrial membrane deformation and therefore disruption occurs through this specific binding. This can be a crucial step in the disease process.
Single-vesicle imaging reveals lipid-selective and stepwise membrane disruption by monomeric α-synuclein
Fredrik Höök, Pernilla Wittung-Stafshede
Added on: 02-10-2021
Novel Alzheimer’s drug candidates
2020
Georg-August University, Göttingen, Germany
The human zinc(II) enzyme glutaminyl cyclase (QC) is suggested to participate in the pathogenesis of Alzheimer’s disease. Using protein crystallography and X-ray structure analyses the authors show snapshots of QC structure and identify hydrazides as highly selective QC inhibitors. Thus, the authors envision a putative use for hydrazydes in Alzheimer's disease, as well as in Huntington's disease and various cancers.
Hydrazides are potent transition-state analogues for glutaminyl cyclase implicated in the pathogenesis of Alzheimer’s disease
Kai Tittmann
Added on: 07-22-2020
SARS-Cov-2 neurotropism in BrainSpheres
2020
Johns Hopkins University School of Medicine, Baltimore, USA
Reports from Wuhan suggest that 36% of COVID-19 patients show neurological symptoms, and cases of viral encephalitis have been reported, suggesting that the virus is neurotropic under unknown circumstances. The authors employ a human induced pluripotent stem cell (iPSC)-derived BrainSphere model, which has been previously used for Zika, Dengue, HIV and John Cunningham virus infection studies. The expression of the ACE2 receptor but not TMPRSS2 was detected in the model. The system allows both virus infection and replication, demonstrating the potential neurotropism of SARS-CoV-2.
Infectability of human BrainSphere neurons suggests neurotropism of SARS-CoV-2
Lena Smirnova
Added on: 07-07-2020
A visual cortex prosthesis for form recognition
2020
Baylor College of Medicine, Houston, USA
The authors developed a visual cortex prosthesis in which shapes were traced on the surface of visual cortex by stimulating electrodes in a dynamic sequence. In both sighted and blind participants, dynamic stimulation enabled accurate recognition of letter shapes predicted by the brain’s spatial map of the visual world. Forms were presented and recognized rapidly by blind participants, up to 86 forms per minute. These findings demonstrate that a brain prosthetic can produce coherent percepts of visual forms.
Dynamic stimulation of visual cortex produces form vision in sighted and blind humans
Daniel Yoshor
Added on: 05-26-2020
Cognitive complaints as an early predictor of dementia
2020
University of New South Wales, Kensington, Australia
The authors examined 873 elderly adults over a six-year period and showed that self-reported cognitive complaints are associated with an increased risk of dementia later in life. Therefore, from a real-world clinical perspective, when older adults present to their general practitioner with memory-specific cognitive complaints, it would be prudent to take this seriously as they can be an early prediction of a decline in global cognition.
Participant and informant memory-specific cognitive complaints predict future decline and incident dementia: Findings from the Sydney Memory and Ageing Study
Katya Numbers
Added on: 05-26-2020
Dementia gene raises risk of severe COVID-19
2020
University of Exeter Medical School, Exeter, United Kingdom
Having a faulty gene linked to dementia doubles the risk of developing severe COVID-19, according to a large-scale study. Data analysis of the UK Biobank showed a high risk of severe COVID-19 infection among European ancestry participants who carry two faulty copies of the APOE gene (termed e4e4). One in 36 people of European ancestry have two faulty copies of this gene, and this is known to increase risks of Alzheimer's disease up to 14-fold and also increases the risk of heart disease.
APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort
David Melzer
Added on: 07-07-2020
The brain uses a minimum effort approach to read text
2020
University of Helsinki, Helsinki, Finland
An information-theoretic model is proposed to explain cognitive resourcing occurring while reading. In a study in which participants read sentences from Wikipedia entries, information gain, a theoretic measure that quantifies the specificity of a word given its topic context, modulates word-synchronised brain activity in the EEG. The effect persists for individual and unseen brain responses since a classifier trained on EEG data can successfully predict information gain from previously unseen EEG. The findings suggest that biological information processing seeks to maximise performance subject to constraints on information capacity.
Information gain modulates brain activity evoked by reading
Tuukka Ruotsalo
Added on: 07-03-2020
Tumor-brain organoid interaction model for disease mechanisms and drug discovery
2020
Berlin Institute of Health and Charité, Berlin, Germany
Glioblastoma (GBM) is the most frequent and most aggressive primary brain tumor with low survival rates despite decades of intensive research. Patient-derived GBM cells are used here to study their invasion into and their interaction with human cerebral organoids. Confocal microscopy and single-cell RNA sequencing are used for the analysis. It was shown that tumor cells extend a network of long microtubes within the normal organoids, recapitulating the in vivo behaviour as this tumor aggressively infiltrates the brain via microtubes. A transcriptional program was identified induced by the interactions between normal brain cells and tumor cells, which upregulates genes required for tumor dispersion. Hence, the model is useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection.
Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics
Roland Eils, Christian Conrad
Added on: 01-29-2021
Neuronal organoids with astrocytes for toxicological studies
2020
Universität Konstanz, Konstanz, Germany
A fast and robust method to generate 3D cultured human dopaminergic neurons (LUHMES) for toxicity testing and long-term culture is presented. A special plating step allows the generation of neurite networks with defined 2D orientation, while all cell bodies (somata) remain in a 3D, dome-like structure. These cultures, named 2.5 dimensional, offer new approaches to quantify toxic effects on organoids by standard technology and high throughput. For instance, the system reacts to the parkinsonian model toxicants MPP+, rotenone, MG-132 and the ferroptosis-inducer erastin. Moreover, stable incorporation of human stem cell-derived astrocytes or microglia is possible. Added astrocytes stabilize the postmitotic state of the LUHMES neurons and thereby allow the formation of a stable microphysiological system. Neuroprotection against the proteasome inhibitor MG-132 and the ferroptosis-inducer erastin by such glia is observed. This exemplifies the crucial protective role of astrocytes in neurodegeneration. The modularity of the system is further employed to incorporate microglia together with astrocytes into the organoids. Such ratio-defined, three cell type-based organoids will allow new approaches to study human pathophysiology and toxicology of the nervous system.
Incorporation of stem cell-derived astrocytes into neuronal organoids to allow neuro-glial interactions in toxicological studies
Marcel Leist
Added on: 07-07-2020
Assessment of developmental neurotoxicity induced by chemical mixtures
2020
Joint Research Centre, Ispra, Italy
This study investigated the developmental neurotoxicity (DNT) induced by chemical mixtures compared to single chemicals. The neurotoxicity was tested on human-induced pluripotent stem cells (hiPSC) that were differentiated into mixed cultures of neurons and astrocytes. Single chemicals showed no toxicity, whereas mixtures of different chemical classes had DNT effects when working in a similar mode of action.
The results show an increased number of neurons and brain-derived neurotrophic factor (BDNF) protein levels, impairment of neurite outgrowth and synaptogenesis. These effects represent autism-like cellular changes. Infants and children are generally co-exposed to mixtures in the environment underscoring the need to implicate this condition in test assays.
Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept
Anna Bal-Price
Added on: 12-02-2020
Brain model reveals neurotoxicological reactions to antidepressiva
2020
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
Using human mini-brains (BrainSpheres), a selective serotonin reuptake inhibitor (SSRI), which is prescribed to pregnant women suffering from depression, has been shown to have a negative effect on the expression of synaptic markers, neurite growth and oligocyte population growth. It has been observed that the use of SSRI during pregnancy is related to neurological abnormalities such as autism in newborns and children. The results obtained with the BrainSpheres suggest that the substance may indeed impair brain development. Thus, the BrainSpheres represent a novel method for toxicity testing and identifying potential developmental neurotoxicants among chemicals and drugs before their entry to the market.
Antidepressant Paroxetine Exerts Developmental Neurotoxicity in an iPSC-Derived 3D Human Brain Model
David Pamies
Added on: 08-28-2020
Functional neuromuscular organoids
2020
Max Delbrück Center for Molecular Medicine, Berlin, Germany
These functional neuromuscular organoids self-organize into spinal cord neurons and muscle tissue, which together form a complex neuronal network that directs muscle tissue to contract. To assess the potential of the neuromuscular organoids to study neuromuscular diseases, a myasthenia gravis model was created. Incubation of the organoids with serum obtained from patients resulted in fewer muscle contractions mirroring the muscle weakness experienced by patients.
Self-organizing 3D human trunk neuromuscular organoids
Mina Gouti
Added on: 05-13-2020
Human neuronal cell culture for pesticide screening
2020
Universidad Complutense de Madrid, Madrid, Spain
The indiscriminate application of Glyphosate may be a concern regarding the possible health and environmental hazards. To investigate the toxic effects of glyphosate and its metabolite AMPA, the human neuroblastoma SH-SY5Y cell line was used. This is an in vitro model to study effects related to neurotoxicity, oxidative stress and neurodegenerative diseases. This study demonstrates that glyphosate and AMPA can induce cell death promoting the involvement of oxidative stress, apoptosis, autophagy and necrosis mechanisms by alteration and /or upregulation of respective genes. The cell culture can serve as a useful model for pesticide screening.
Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways
Marta Martínez, Arturo Anadón
Added on: 08-16-2023
Astrophysics and AI key to early dementia diagnosis
December 2019
Brighton and Sussex Medical School, Brighton, United Kingdom
A computer program, developed at Brighton and Sussex Medical School together with astrophysicists, helps in early diagnosis of dementia. Using patient data from general practitioners, 70 indicators related to the onset of dementia and recorded in the five years prior diagnosis were found. This machine learning model identified 70% of dementia cases before the physician.
Identifying undetected dementia in UK primary care patients: a retrospective case-control study comparing machine- learning and standard epidemiological approaches
Elizabeth Ford
Elizabeth Ford et al. BMC Medical Informatics and Decision Making 2019 [330]
Technology Networks [331]
Added on: 07-07-2020
Animal-free testing of lethal neurotoxins
October 2019
School of Biological Sciences, University of Queensland, St. Lucia, St. Lucia, Australia
The approach enables screening of venoms including snake venoms for the development of anti-venoms and drugs. The binding to these probes is measured by analysing changes in the light reflected back. The technology relies on the design of synthetic peptides that correspond to neuronal receptors mediating muscle contraction. Venoms bind to the synthetic peptides more vigorously than they do to human nerve receptors. This method for testing of paralytic neurotoxins uses optical probes dipped into a solution containing the venoms.
A taxon-specific and high-throughput method for measuring ligand binding to nicotinic acetylcholine receptors
Bryan Fry
Added on: 04-30-2020
Using deep learning artificial intelligence to model cognitive function
October 2019
Brain Institute, Florida Atlantic University, Boca Raton, USA
By putting neural networks in robots, researchers are able to build models of complex cognitive functions such as perception, attention, and curiosity, experiment on them, and immediately get feedback directly from the neural network about decision-making behaviour. In this novel approach dubbed “robopsychology,” they have demonstrated the potential for synergistic research utilizing behavioural, computational, and neural techniques that could be crucial for advancing treatments and prevention strategies for mental conditions such as schizophrenia and Alzheimer´s disease.
Using deep learning artificial intelligence in robots to model cognitive function
William Hahn
Added on: 07-08-2020
Autologous four-organ-chip
Company 2019
TissUse GmbH, Berlin, Germany
In this study, a four-organ-chip interconnecting miniaturized human intestine, liver, brain and kidney equivalents was investigated. All four organ models were predifferentiated from induced pluripotent stem cells from the same healthy donor and integrated into the microphysiological system. Coculture of the four autologous tissue models in one common medium deprived of tissue-specific growth factors was successful over 14 days. Intestine, liver and neuronal model maintained defined marker expression. The renal model was overgrown by coexisting cells and did not further differentiate.
Autologous induced pluripotent stem cell-derived four-organ-chip
Anja Patricia Ramme
Added on: 12-23-2020
Black phosphorus used for artificial intelligence
2019
RMIT University, Melbourne, Australia
Layered black phosphorus (BP), a promising 2D material, tends to oxidize under ambient conditions. New opportunities arise from intrinsic BP defects: It is the only material with the ability to distinguish between UV-A and UV-B radiation, thus having tremendous implications for skin health management. The same setup is utilized to show an optically stimulated mimicry of synaptic behaviour. It mimics action potentials, analogous to the neuronal activities triggered by optical stimuli in biological neurons. As such, few-layers BP renders mimicry of different synaptic functions in biological neurons and light-sensitive cells, such as retinal ganglion cells. This provides new possibilities in neuromorphic computing. Furthermore, it is shown that serially connected devices can perform digital logic operations using light. Thus, a BP-based electronic chip mimicking the human brain that uses light to create and modify memories could be created.
Multifunctional optoelectronics via harnessing defects in layered black phosphorus
Taimur Ahmed, Sumeet Walia
Added on: 07-09-2020
Differences in neurons, derived from stem cells of schizophrenia or autism patients
2019
University of Tübingen, Reutlingen, Germany
HiPSC-derived neurons from healthy control individuals
as well as from patients with schizophrenia and autism were tested in a panel of assays, including quantification of synaptic markers, measurement of neurite outgrowth, analysis of calcium signals as well as transcriptome analysis. The results are useful to discriminate autism and schizophrenia phenotypes in hiPSC-derived neurons derived from different patients.
Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism
Hansjürgen Volkmer
Added on: 07-09-2020
3D-Brainspheres as model for nanoparticle-associated substances
2019
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
Nanoparticles (NP) can cross the blood-brain-barrier (BBB) and accumulate in different areas of the central nervous system (CNS), thus are potential tools to carry drugs and treat brain disorders. The effects of different NP were studied in human LUHMES cell line (3D LUHMES) and human iPSC-derived brain spheroids (BrainSpheres). The simpler, single-cell model was more sensitive to the toxic effects, in line with the lack of glia support to neurons. In BrainSpheres the NP, especially modified with specific ligands, can cross the BBB and show higher levels due to the presence of glial cells whose function is to facilitate uptake. Nevertheless, decrease of viability or morphological alterations was not observed, maybe due to activation of cell survival programs.
Therefore, 3D brain spheroid models incorporating microglia are well suited to comparatively characterize NP neurotoxicity. The use of multiple models, which encompass simplicity and physiological relevance, serves as a tool for more NP drug-delivery focused research.
Suitability of 3D human brain spheroid models to distinguish toxic effects of gold and poly-lactic acid nanoparticles to assess biocompatibility for brain drug delivery
Lena Smirnova
Added on: 08-28-2020
Blood-brain barrier chips enable disease modeling
2019
The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, USA(1)
The Department of Physiology and Cell Biology and the Regenerative Medicine and Stem Cell (RMSC) Res, Be`er Sheva, Israel(2)
The Department of Physiology and Cell Biology and the Regenerative Medicine and Stem Cell (RMSC) Res, Be`er Sheva, Israel(2)
This iPSC-derived blood-brain barrier chip exhibits physiologically relevant transendothelial electrical resistance and accurately predicted blood-to-brain permeability of pharmacologics. Chips created from individuals with neurological diseases predicted disease-specific lack of transporters and disruption of barrier integrity.
Human iPSC-derived blood-brain barrier chips enable disease modeling and personalized medicine applications
Clive N. Svendsen(1), Gad D. Vatine(2)
Added on: 05-06-2020
Blood-brain-barrier chip recapitulates shuttling of drugs and antibodies
2019
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, USA
This multifluidic blood-brain-barrier-on-a-chip model contains a human iPSC-derived brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes. The model recapitulates the barrier function of the in vivo human blood-brain-barrier for at least one week in culture. The endothelium displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished including a period of differentiation under hypoxic conditions.
Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies
Donald E. Ingber
Added on: 05-05-2020
New combined method for imaging neuronal brain activity
2019
Max Planck Institute for Human Development, Berlin, Germany(1)
Princeton University, Princeton, USA(2)
Princeton University, Princeton, USA(2)
Participants' brains were studied by functional magnetic resonance imaging signals after they had learned a decision-making task. During a subsequent resting phase, the replay of activity patterns in the hippocampus reflected the order of previous task-state sequences at a higher speed. Thus, sequential hippocampal reactivation might participate in human decision-making. The results support the importance of sequential reactivation in the human hippocampus for nonspatial decision-making and establish the feasibility of investigating such rapid signals with fMRI (functional magnetic resonance imaging), despite substantial limitations in temporal resolution. To date, a non-invasive, human-based method to measure fast brain activities was lacking. By combining this MRI technique with an algorithm for the detection of activity pattern, a method was developed for studying human brain processes.
Sequential replay of nonspatial task states in the human hippocampus
Nicolas W. Schuck(1), Yael Niv(2)
Added on: 07-09-2020
iPSC brain endothelial cells as a model to study Neisseria meningitidis infection
2019
University Hospital Wuerzburg, Wuerzburg, Germany(1)
University of Wuerzburg, Wuerzburg, Germany(2)
University of Wuerzburg, Wuerzburg, Germany(2)
Meningococcal meningitis is a severe infection of the central nervous system that occurs when the pathogen Neisseria meningitidis (Nm) invades the brain endothelial cells (BECs) of the meningeal blood-liquor barrier. The human specificity of Nm and the lack of robust BEC phenotypes in currently used models highlight the need for new models with properties more consistent with BECs in vivo. Here, the researchers demonstrate the utility of iPSC-BECs in vitro to study Nm infection. In addition, host expression patterns in response to Nm infection were profiled by selecting specifically infected iPSC-BECs and sequencing their transcriptome. Overall, this model provides new insights into Nm pathogenesis, including the effects of Nm on barrier properties and tight junction complexes, and suggests that the paracellular pathway may contribute to the traversal of BECs by Nm.
Induced pluripotent stem cell-derived brain endothelial cells as a cellular model to study Neisseria meningitidis infection
Antje Appelt-Menzel(1), Brandon J. Kim(2), Alexandra Schubert-Unkmeir(2)
Added on: 07-07-2022
Alzheimer in mini brains
2019
Ruhr University Bochum, Bochum, Germany
Despite intensive research, the cause of the plaque deposits in the brain in Alzheimer's patients has still not been found. At the University of Bochum, mini brains are now used to answer this question. The researchers genetically modify the stem cells from which the minibrains are made by inserting fluorescent markers at specific genetic locations. For example, by inserting these markers right at the beginning and end of the gene sequence that contains the blueprint for the protein that is deposited in Alzheimer's, they can later track exactly where the protein or its cleaved parts is located. This allows the results obtained in cell culture to be checked in a more human-relevant system.
Alzheimer im Mini-Gehirn
Thorsten Müller
Added on: 05-25-2020
Impact of modified proteins in multiple sclerosis studied using patients' samples
2019
University Hospital Zurich, Zürich, Switzerland
In Multiple Sclerosis (MS), a chronic inflammatory autoimmune disease of the central nervous system (CNS), the amount of the citrullinated proteins is increased in white matter. In the present study, the researchers investigated the presence of citrulline in proteins of brain tissues from MS patients and controls. Then, the researchers assessed in vitro the immune response of T cells isolated from donors to citrullinated and unmodified proteins. The study establishes a map of citrullinated proteins in human brain tissue and shows that the number of modified proteins in MS white matter was higher than in control tissue. The approach developed here allows a deep analysis of the proteome of small tissue samples and the testing of the impact of modified proteins in the immune response.
Brain citrullination patterns and T cell reactivity of cerebrospinal fluid-derived CD4+ T cells in multiple sclerosis
Roland Martin
Added on: 10-29-2021
Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons
2019
The Salk Institute for Biological Studies, La Jolla, USA
Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant, and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In this study of a well-characterized cohort of over 800 MDD patients, iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR) were generated. The authors studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. The results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.
Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons
Fred H. Gage
Added on: 05-09-2023
Bioprinted glioblastoma-on-a-chip
2019
Pohang University of Science and Technology, Pohang, South Korea(1)
Seoul National University College of Medicine, Seoul, South Korea(2)
Seoul National University College of Medicine, Seoul, South Korea(2)
Within this study, a bioprinted glioblastoma tumor model consisting of patient-derived tumor cells, vascular endothelial cells and decellularized extracellular matrix is demonstrated. The model is integrated into a concentric-ring structure that sustains a radial oxygen gradient, and recapitulates the structural, biochemical and biophysical properties of the native tumors. It was shown that the glioblastoma-on-a-chip reproduces clinically observed patient-specific resistances to treatment with concurrent chemoradiation and chemotherapy, and that the model can be used to identify drug combinations associated with superior tumor killing.
The patient-specific tumor-on-a-chip model might be useful for the identification of effective treatments for glioblastoma patients resistant to the standard treatment.
A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy
Dong-Woo Cho(1), Sun Ha Paek(2)
Added on: 04-04-2023
Human cerebral organoids for the analysis of neuronal heterotopia
2019
Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany(1)
Max Planck Institute of Psychiatry, München, Germany(2)
Max Planck Institute of Psychiatry, München, Germany(2)
The authors study periventricular heterotopia (PH) by analyzing cerebral organoids derived from iPSCs of patients with certain mutations or from isogenic knockout lines. Cerebral organoids reproduce the cortical heterotopia associated with PH and a single-cell RNA-sequencing approach reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. A defective neural progenitor cell morphology and an altered navigation system in a subset of neurons can, therefore, underlie this form of PH.
Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia
Barbara Treutlein(1), Silvia Cappello(2)
Added on: 05-25-2020
3D brain cancer platform for personalized medicine
Company 2019
MicroMatrices Associates Ltd, Dundee, United Kingdom
A high throughput histology platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.
A human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine
Simon Plummer
Added on: 05-25-2020
Leigh syndrome research with induced pluripotent stem cells.
2019
Charité - Universitätsmedizin, Berlin, Germany(1)
Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany(2)
Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany(2)
In order to dissect the molecular mechanisms underlying the neuronal pathology in Leigh syndrome (LS) patients carrying homozygous SURF1 mutations (LS SURF1), induced pluripotent stem cells from LS SURF1 patients (SURF1 iPS) were generated. Neuronal cultures and cerebral organoids derived from SURF1 iPS exhibited features indicative of impaired neurogenesis. Bioenergetic dysfunction occurred already at the level of neural progenitor cells (NPCs), and led to defects in neuronal generation and maturation, disrupting the branching capacity and firing activity of neurons. Biallelic correction of SURF1 mutation via CRISPR/Cas9 genome editing reverted the phenotypes. The data imply that LS SURF1 causes a failure in the development of maturing neurons. The authors employed NPC function as an interventional target and discovered that wild-type SURF1 over-expression was effective in improving NPC bioenergetics and promoting neurogenesis. Altogether, the authors propose aberrant neurogenesis as a central pathogenetic mechanism in LS SURF1 and suggest a potential strategy for restoring neuronal function in the fatal pediatric disease Leigh syndrome.
SURF1 mutations causative of Leigh syndrome impair human neurogenesis
Markus Schülke(1), Nikolaus Rajewsky(2), Alessandro Prigione(2)
Added on: 04-15-2021
Regional protein expression in human Alzheimer’s brain correlates with disease severity
2019
The University of Manchester, Manchester, United Kingdom
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide, with no effective treatment available. The development of AD follows a distinctive pattern in the brain. In this study, functionally distinct human brain regions were shown to display varying and region-specific changes in protein expression. These changes provide insights into the progression of disease, novel AD-related pathways, the presence of a gradient of protein expression change from less to more affected regions and a possibly protective protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and open new avenues to enhance molecular understanding of AD pathophysiology, provide new targets for intervention and broaden the conceptual frameworks for future AD research.
Regional protein expression in human Alzheimer’s brain correlates with disease severity
Richard D. Unwin
Added on: 08-05-2024
A patient-derived iPSC-based ALS model
2019
Harvard University, Cambridge, USA
A patient-derived iPSC-based ALS model highlights the roles of the RNA-binding protein TDP-43 and of the microtubule regulator STMN2 in ALS pathogenesis.
ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
Kevin Eggan
Added on: 05-25-2020
Assembling human brain organoids
2019
Stanford University, Stanford, USA
The author discusses the emerging approaches to produce brain assembloids — the next generation of brain organoids that combine multiple cell lineages in 3D. These cultures can be used to model interactions between various brain regions in vitro, and ultimately may be applied to understand the assembly of neural circuits and to capture complex cell-cell interactions in the brain. This enables research into human brain development and neuropsychiatric and neurodegenerative diseases such as Alzheimer's.
Assembling human brain organoids
Sergiu P. Paşca
Added on: 05-25-2020
MRI reveals the secrets of temporal memory
2019
University of California, Irvine, USA
In a UCI study, participants sat with their heads inside a high-resolution fMRI scanner while watching a popular TV show and then viewing still frames from the episode, one at a time. This way it was possible to capture the processes by which the brain stores information about when events happen, known as temporal memory. The researchers identified a new network of brain regions involved in these processes, where the nerve cells give each moment a distinctive signature. This research may further our understanding of dementia, as these temporal memory regions are the first to experience age-related deficits and also show some of the first pathological hallmarks of Alzheimer’s disease.
Precise temporal memories are supported by the lateral entorhinal cortex in humans
Michael A. Yassa
Added on: 07-09-2020
Serotonin-induced hyperactivity in neurons from SSRI-resistant depressive patients
2019
The Salk Institute for Biological Studies, La Jolla, USA
Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In this study from a large cohort of well-characterized MDD patients, the authors have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. Serotonergic neurotransmission in patient forebrain neurons in vitro were studied and the authors observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. This data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.
Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons
Fred H. Gage
Added on: 05-10-2023
Sporadic Alzheimer’s Disease in a dish
2019
Harvard Medical School, Boston, USA
The molecular basis of the earliest neuronal changes leading to Alzheimer's disease (AD) is unclear. The aim of this study was to explore the pathogenesis of sporadic Alzheimer's disease (SAD). For this purpose, neural progenitor cells (NPs) generated from iPSCs of SAD patients were compared with those from healthy volunteers and NPs genetically engineered to express APOE4, a common genetic AD risk factor.
These iPSC-derived neural progenitor cells (NPs) and neurons were found to differ in gene networks related to neuronal differentiation, neurogenesis and synaptic transmission. The iPSC-derived neuronal cells from SAD patients showed accelerated neuronal differentiation and reduced progenitor cell renewal. A similar phenotype was also seen in NP cells and cerebral organoids derived from APOE4-iPSCs. It was demonstrated that impaired function of the transcriptional repressor REST is significantly involved in the altered transcriptome and differentiation state. Thus, the dysregulation of neuronal gene networks could set in motion the pathological cascade that leads to Alzheimer's disease.
REST and neural gene network dysregulation in iPSC models of Alzheimer’s disease
Bruce A. Yankner
Added on: 02-24-2022
Body-on-a-chip system viable for 28 days
CompanyDecember 2018
Hesperos Inc., Orlando, USA
The study describes a serum-free 4-organ system consisting of human heart, liver, skeletal muscle and nervous system that maintain cellular viability and function over 28 days. Noninvasive electrical evaluation can be performed for neurons and cardiac cells and mechanical determination for cardiac and skeletal cells. The system offers an alternative to the repeat dose toxicity animal tests and for the monitoring of multiorgan function upon long-term chemical exposure.
Long‐term electrical and mechanical function monitoring of a human‐on‐a‐chip system
James J. Hickman
Added on: 05-25-2020
Human brain model to study Dengue and Zika virus
December 2018
Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
It is shown that brain organoids containing microglia cells in addition to astrocytes, oligodendrocytes and neuronal populations possess physiologically relevant features. Without these cells, the organoids do not show inflammatory reactions to e.g. lipopolysaccharides (LPS) or flaviviruses. By co-cultivation with microglia cells, the gene expression of inflammatory cytokines is induced in the brain organoids. After infection with Zika and Dengue viruses interleukins, tumor necrosis factor alpha (TNF-α) and chemokines are also induced.
This shows that the model is physiologically relevant and has potential applications in research on infectious disease and host-pathogen interactions.
Microglia Increase Inflammatory Responses in iPSC-Derived Human BrainSpheres
David Pamies
Added on: 08-28-2020
Factors controlling immune cells studied in cells isolated from patients with multiple sclerosis
November 2018
Rafsanjan University of Medical Sciences, Rafsanjan, Iran
Multiple Sclerosis (MS) results in the demyelination of neurons within the brain and spinal cord due to inflammatory and autoimmune reactions. The disease is caused by self-reactive Th1 lymphocytes, while Th2 cells may confer protection. Both cell types, Th1 and Th2, are derived from the same naïve cells in a process controlled by specific cellular transcription factors called T-bet and GATA-3. In the present study, the researchers aimed at uncovering the T-bet and GATA-3 expression level in immune cells isolated from MS patients. The data show that the T-bet expression was enhanced, while the GATA-3 expression diminished. These results probably indicate an imbalance in Th1/Th2 cells in the level of transcription factors with a tendency toward Th1 cells in MS. The clinical utilization of the transcription factors as novel biomarkers of MS should be evaluated in further studies.
Different expressions of specific transcription factors of Th1 ( T-bet) and Th2 cells ( GATA-3) by peripheral blood mononuclear cells from patients with multiple sclerosis
Abdollah Jafarzadeh
Added on: 10-30-2021
Functional and sustainable 3D human neural network models
October 2018
Tufts University, Medford, USA
3D CNS cell cultures were generated from samples of Alzheimer's and Parkinson's patients´ iPSCs. The cultures consisted of diverse cell populations and exhibited spontaneous neural over nine months. These models structurally and functionally mimic the characteristics of the brain and enable the study of cell interactions, disease progression and the response to treatments for individual patients.
Functional and sustainable 3D human neural network models from pluripotent stem cells
David L. Kaplan
William L. Cantley et al. ACS Biomaterials Science & Engineering 2018 [370]
Technology Networks [371]
Added on: 05-25-2020
Organ-on-chip model of the human neurovascular unit
October 2018
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, USA
The authors modelled the human neurovascular unit (NVU) using microfluidic organ chips, allowing analysis of the roles of individual cell types in NVU functions. Three coupled chips modelled the influx across the blood–brain barrier (BBB), the brain parenchymal compartment and efflux across the BBB. The system mimicked the effect of intravascular administration of the psychoactive drug methamphetamine and a previously unknown metabolic coupling between the BBB and neurons was identified. This system offers an in vitro approach for probing transport, efficacy, mechanism of action and toxicity of neuroactive drugs.
A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells
Kevin Kit Parker, Donald E. Ingber
Added on: 05-25-2020
Brain scans show brain aging over the course of life depending on diseases and lifestyle
2018
Amen Clinics, Costa Mesa, USA
A large psychiatric cohort of 31,227 individuals received brain SPECT (Single Photon Emission Computed Tomography) at rest and during a concentration task. ANOVA (Analysis of Variance) was done to identify the mean age trends over the course of the age range in this group, 0-105 years. A regression model in which brain SPECT regions of interest were used to predict chronological age (CA) was then utilized to derive brain estimated age (BEA). The difference between CA and BEA was calculated to determine increased brain ageing in common disorders such as depression, dementia, substance use, and anxiety. Throughout the lifespan, variations in perfusion were observed in childhood, adolescence, and late-life. Increased brain ageing was seen in alcohol use, cannabis use, anxiety, bipolar, schizophrenia, attention-deficit/hyperactivity disorder, and in men. Brain SPECT can predict chronological age and this feature varies as a function of common psychiatric disorders.
Patterns of regional cerebral blood flow as a function of age throughout the lifespan
Daniel G. Amen
Added on: 07-09-2020
Human blood-brain barrier co-culture model mimicking the neurovascular unit
2018
University Hospital Wuerzburg, Wuerzburg, Germany
Human in vitro models of the blood-brain barrier (BBB) are a promising tool for drug development and understanding mechanisms in health and disease. This study addresses the generation of a neurovascular unit (NVU) by standard differentiation of adherent hiPS cells into BBB endothelial cells and neural stem cells (NSCs). Both cell types are combined with primary astrocytes and pericytes to develop complex, physiological BBB in vitro models. The endothelial cells in the apical compartment of the transwell models are separated from the basolateral seeded co-culture mixture by a synthetic membrane, which simplifies analyses. The integrity and functionality of the endothelial barrier are enhanced by the specific mixture of NVU niche cells, as determined here by decreasing paracellular permeability of sodium fluorescein and measuring transendothelial electrical resistance (TEER).
Establishment of a human blood-brain barrier co-culture model mimicking the neurovascular unit using induced pluripotent stem cells
Antje Appelt-Menzel
Added on: 07-07-2022
Rotenone's toxicity in a human brain model
2018
Johns Hopkins University, Baltimore, USA
Recent evidence suggests that the prevalence of neurodevelopmental disorders is increasing in the last decades. Several studies have shown that this could be related to higher exposure to toxic chemicals that exert developmental neurotoxicity. However, the limitations in routine toxicity tests make it difficult to assess the dangers of all the existing chemicals. Nowadays, human iPSC are arising as a potential cost-effective alternative to build human platforms to perform toxicity assays. In this study, BrainSpheres, a human 3D platform based on multicellular brain spheroids derived from human iPSCs, is used to test rotenone's toxicity during neurodevelopment. The results showed that the toxicity of rotenone varies along the differentiation status, inducing higher oxidative stress levels at the early stages of the differentiation. Morphological analyses also showed that dopaminergic cells had higher sensitivity to rotenone's cytotoxicity than other cell types. Finally, the researchers show that exposure to rotenone induced changes in neurodevelopmental pathways that could potentially link to previously demonstrated effects of this toxic compound. Here, the BrainSpheres human platform is validated as a tool to study neurotoxicity and developmental defects, which is used to elucidate the neurotoxicity of rotenone and propose some key mechanisms associated to it.
Rotenone exerts developmental neurotoxicity in a human brain spheroid model
Helena T Hogberg
Added on: 09-02-2021
Amyloid beta detection with curcumin
2018
VU University Medical Center Alzheimer Center, Amsterdam, Netherlands
Alzheimer's disease is one of the most prevalent neurodegenerative diseases. However, tools to diagnose and control the evolution of the disease are still scarce. Recently, it has been shown that curcumin has amyloid binding and fluorescent properties. Yet, the dynamics of its interactions with Alzheimer's pathological processes are still not well-known. In this study, different forms of curcumin were used to target deposits in post-mortem brain samples of different neurodegenerative diseases patients and they were compared to currently used staining methods. The researchers found that curcumin binds to amyloid-beta aggregations in Alzheimer's disease and cerebral amyloid angiopathy, but not to other protein aggregates in other neuropathologies. Immunohistochemical staining confirmed that curcumin binds to fibrillar amyloid-beta and cored plaques. Overall, it is shown that curcumin and its derivates bind selectively to fibrillar amyloid-beta and, given that curcumin is a food additive, it has a promising potential in being used coupled with imaging techniques in in vivo diagnostics in Alzheimer's disease.
Different curcumin forms selectively bind fibrillar amyloid beta in post mortem Alzheimer’s disease brains: Implications for in-vivo diagnostics
Jurre den Haan
Added on: 08-27-2021
Improvement of a therapeutic strategy for neuronal survival
2018
Karolinska Institutet, Stockholm, Sweden
Alzheimer's disease pathology involves early degeneration of cholinergic neurons and decreased levels of the nerve growth factor (NGF). Encapsulated cell technology to deliver NGF to the affected area and promote neuronal survival has already been tested in clinical trials. However, the results showed variability of encapsulated cells survival and NGF release. Here, an NGF overproducing human immortalized retinal epithelial cell line is treated with amyloid-beta peptides, interleukin 1 beta and the cerebrospinal fluid of patients with Alzheimer's disease, Lewy body dementia or subjective cognitive impairment to decipher the cause of low cell viability during the human trials. Only interleukin 1 beta had an impact on nerve growth factor production and the cerebrospinal fluid of Alzheimer's patients was more detrimental to NGF production than others. Three proteins involved in inflammation were differentially expressed in Alzheimer's patients cerebrospinal fluid, suggesting that it is responsible for the variability in survival of encapsulated cells. This human model allowed the researchers to identify key mechanisms influencing the success of their therapeutic strategies that can be further studied to improve the outcome of their treatment.
Cerebrospinal fluid from Alzheimer patients affects cell-mediated nerve growth factor production and cell survival in vitro
Homira Behbahani
Added on: 08-16-2021
Personalized brain network mapping in autism research
2018
University of Toronto, Toronto, Canada
The Personalized Intrinsic Network Topography (PINT) is a novel approach for localizing individually specific resting-state networks using conventional fMRI scans. Using this method, the authors describe a greater variability in the spatial locations of resting-state networks within individuals with autism spectrum disorder (ASD) compared to healthy individuals. PINT can be used for personalized measuring of altered brain functioning in neurodevelopmental disorders and estimating the developmental course, phenotypic heterogeneity, and treatment response.
Personalized intrinsic network topography mapping and functional connectivity deficits in autism spectrum disorder
Aristotle N.Voineskos
Added on: 05-25-2020
Spheroids to study cancer stem cells
2018
Ankara University, Ankara, Turkey
Cancer stem cells have become a popular subject of study. To better understand their properties, it is necessary to improve the current in vitro models. Here, a 3D in vitro system is used to analyse the cancer stemness of a human breast cancer cell line and a human glioblastoma cell line. The results showed that breast cancer cells were able to form uniform 3D structures and acquired cell stem cell features. Targeting cancer stem cells with metformin reduced the expression of genes related to drug resistance. Furthermore, it also increased the effectiveness of 5-fluorouracil. Overall, the researchers demonstrate that the use of 3D models in vitro can improve the translationality of cancer models, as they help replicate tumour microenvironments and have diverse cellular populations as it occurs in vivo.
Evaluation of cancer stemness in breast cancer and glioblastoma spheroids in vitro
Açelya Yilmazer
Added on: 10-18-2021
In vitro studies to understand inflammation in neuromyelitis optica spectrum disorder
2018
Medical University of Lodz, Lodz, Poland
Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system (CNS) inflammatory autoimmune illness leading to paralysis and blindness. Autoantibodies against astrocytes have been detected in the majority of NMOSD cases. In this study, the researchers aimed at understanding the mechanisms triggering inflammation, impairment of astrocyte function, and the role of neutrophils. They used a model based on in vitro culture of human astrocyte line and neutrophils isolated from healthy individuals supplemented with serum from NMOSD patients. The data showed the pathogenic capacity of the NMOSD serum, it also confirmed the role of autoantibodies and the interplay between astrocytes and neutrophils.
C5a-preactivated neutrophils are critical for autoimmune-induced astrocyte dysregulation in neuromyelitis optica spectrum disorder
Przemysław Lewkowicz
Added on: 10-28-2021
iPSC-based model for Parkinson pathogenesis
2018
Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
The authors employ human induced pluripotent stem cells (iPSCs) from Parkinson patients to elucidate the role of a-Synuclein (a-Syn) in neurodegeneration. The study shows that a-syn oligomers cause synaptic degeneration and neuron toxicity, and thus may represent a putative therapeutic target.
α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies
Iryna Prots
Added on: 05-25-2020
Nanoparticles to detect and inhibit β-amyloid aggregation
2018
Universidad de Chile, Independencia, Chile(1)
Universidad Tecnológica Metropolitana, San Joaquín, Chile(2)
Universidad Tecnológica Metropolitana, San Joaquín, Chile(2)
A microfluidic system is used to generate magneto-plasmonic nanoparticles coupled with peptide D1, which selectively binds to β-amyloid peptides associated with Alzheimer's disease. Afterwards, these nanoparticles were treated to reduce cytotoxicity, as demonstrated by the high cell viability in cytotoxic assays performed on a human neuroblastoma cell line. Overall, these nanoparticles inhibit fibril formation and aggregation, thus they could be potential therapeutic and diagnostic tools for Alzheimer's disease.
Peptide functionalized magneto-plasmonic nanoparticles obtained by microfluidics for inhibition of β-amyloid aggregation
M J Kogan(1), N Hassan(2)
Added on: 08-04-2021
3D multicellular microfluidic platform to model neurodegenerative diseases
2018
University of North Carolina at Charlotte, Charlotte, USA
Mechanisms of Alzheimer's disease pathology remain poorly understood. In this study, the researchers develop a 3D multicellular model that integrates human neuronal cells, astrocytes and microglia in a microfluidic platform. This system recapitulated the key hallmarks of the disease that involved the different cell types present in the model, allowing the study of intercellular interactions relevant for the pathophysiology of Alzheimer's disease. In conclusion, this new model can help to develop better human brain models for mechanistic studies of neurodegenerative diseases that involve neuro-glial interactions and improve drug discovery.
A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease
Hansang Cho
Added on: 08-04-2021
Biophysical cues to optimize dopaminergic neurons production
2018
Duke-NUS Medical School, Singapore, Singapore(1)
University of Waterloo, Waterloo, Canada(2)
University of Waterloo, Waterloo, Canada(2)
Parkinson's disease is a neurodegenerative disorder that leads to the progressive death of dopaminergic neurons. In the last years, cell replacement therapies have shown to have great potential as therapeutic strategies for this disease, with yet no cure. However, the available approaches to obtain high quality and big quantities of cells for transplantation applications is still challenging. Here, biophysical cues have been used to enhance differentiation and maturation towards dopaminergic cells from human induced pluripotent stem cells. Different topographical patterns were applied during differentiation and maturation stages, and the researchers found that specific patterns were beneficial for initial lineage commitment and others increased neural complexity and functionality at terminal stages of maturation. The different biophysical cues were also able to produce functional dopaminergic neurons from Parkinson's patients with specific mutations. Overall, the researchers propose the inclusion of topographical patterns as an optimization step towards the refinement of differentiation protocols for cell therapy strategies and modelling of Parkinson's disease.
Sequential application of discrete topographical patterns enhances derivation of functional mesencephalic dopaminergic neurons from human induced pluripotent stem cells
Eyleen L K Goh(1), Evelyn K F Yim(2)
Added on: 09-01-2021
Deep brain stimulation improves speech performance in a Parkinson context
2018
RWTH Aachen University, Aachen, Germany
Parkinson's disease is a neurodegenerative disorder that leads to motor deficits, including speech. Although currently there is no effective treatment to stop the disease, deep brain stimulation in the subthalamic nucleus and globus pallidus internus has been described as an effective therapy. Here, a neural model is developed to evaluate the effects in speech performance of different dopamine levels in the striatum and activity levels in the subthalamic nucleus and the globus pallidus internus through syllable repetition task simulation. The results show that a decrease of dopamine levels in the striatum leads to different degrees of syllable sequencing errors, as seen in Parkinson's disease, which could be counteracted by a reduction in the activity in the subthalamic nucleus or the globus pallidus internus. The model developed in this study relates the reduction in syllable sequencing errors to the inhibition of the subthalamic nucleus and globus pallidus internus, which may bring new insights into the mechanisms by which deep brain stimulation improves speech performance in Parkinson's patients.
Inhibiting basal ganglia regions reduces syllable sequencing errors in Parkinson's disease: a computer simulation study
Bernd J Kröger
Added on: 09-24-2021
Depression impairs new as well as old memories
2018
Ruhr University Bochum, Bochum, Germany
Researchers created a computational model to simulate the brains of patients suffering from depression and showed that depressive episodes can impair both recent memory storage and retrieval by limiting the formation of new brain cells. In addition, it also showed that depressive episodes can erase past stored memories.
The reduction of adult neurogenesis in depression impairs the retrieval of new as well as remote episodic memory
Sen Cheng
Added on: 05-25-2020
Development of a human in vitro model of the blood-brain barrier
2018
Rutgers University, Piscataway, USA(1)
University of Nebraska Medical Center, Omaha, USA(2)
University of Nebraska Medical Center, Omaha, USA(2)
A healthy blood-brain barrier is essential for proper homeostasis of the central nervous system. Thus, physiological deficiencies in it can have important roles in several brain pathologies. In the last years, there have been advances in developing in vitro models of the blood-brain barrier but there are still a lot of limitations associated with them. Here, a 3D printed transwell plate is used to create a bilayer co-culture of human iPSC-derived endothelial cells and astrocytes. Co-culture with astrocytes promoted tight junction protein expression and electrical resistance of the bilayer. Expression of tight junction proteins in this model suggested the formation of a cellular barrier, which was confirmed by transendothelial electrical resistance measurements, but also having permeability properties as shown by sodium fluorescein assay. Finally, researchers used a human glioblastoma cell line to study the barrier dynamics when using paclitaxel and bortezomib and human iPSC-derived neural cells to test how the model behaved when applying amyloid-beta. Overall, this extensive study proposes a new integrative human model for the blood-brain barrier that can be a powerful tool to increase translationality of in vitro studies.
Establishment of a human iPSC- and nanofiber-based microphysiological blood–brain barrier system
Peng Jiang(1), Bin Duan(2)
Added on: 08-18-2021
Human neuromuscular junction (NMJ) two-organ model for evaluation of therapeutics
Company 2018
Hesperos Inc., Orlando, USA
A 2-organ-on-a chip system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium. The system is composed of two chambers linked by microchannels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological neuromuscular junction (NMJ) function. Three dose-response curves were generated to demonstrate the pharmacological relevance of the system. This quantifiable functional human NMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs.
Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics
James J. Hickman
Added on: 05-25-2020
Machine learning helps predict schizophrenia treatment outcomes
2018
Chinese Academy of Sciences, Beijing, China
A machine learning algorithm is used to examine fMRI images of both newly diagnosed, previously untreated schizophrenia patients and healthy subjects. By measuring the connections of a brain region called the superior temporal cortex to other regions of the brain, the algorithm successfully identified patients with schizophrenia at 78 per cent accuracy. It also predicted with 82 per cent accuracy whether or not a patient would respond positively to a specific antipsychotic treatment named risperidone. The researchers hope to expand the work to include other mental illness such as major depressive and bipolar disorders.
Treatment response prediction and individualized identification of first-episode drug-naïve schizophrenia using brain functional connectivity
Xiang Yang Zhang
Added on: 07-06-2020
Multicellular microfluidic model of the blood-brain barrier
2018
University of Leeds, Leeds, United Kingdom
The blood-brain barrier is essential for the homeostasis of the central nervous system. Disruption of the blood-brain barrier is observed in many neurodegenerative diseases. Therefore, is utterly important to develop human models that allow studying the mechanisms of the different cell types involved in the functioning of the blood-brain barrier. Here a microfluidic co-culture system is presented that contains human primary endothelial cells, pericytes and astrocytes in separated chambers to study the optimal conditions of the culture of each cell type and the paracrine interactions between them. Furthermore, the researchers are able to explore the effects of an amyloid-beta peptide in this setup, showing that it can be used to investigate mechanisms and therapies of neurodegenerative diseases. The results show that this newly developed model can be a powerful tool to study in vitro the individual cellular components of the human blood-brain barrier and the effects of disease-associated metabolites in them.
A novel dynamic multicellular co-culture system for studying individual blood-brain barrier cell types in brain diseases and cytotoxicity testing
Sikha Saha
Added on: 08-19-2021
Neuronal cell mechanisms against toxic exposure
2018
Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
Toxicologic studies performed in vitro often rely on exposure to tested compounds at high concentrations for short times. But these conditions are not those found usually in real-life exposures, which are usually at low doses for long term periods. Here, an in vitro 3D model of human dopaminergic cells is used to study the exposure to rotenone and study the acute response and the long-term adaptations in cells. When exposed to the toxic compound, dopaminergic cells underwent several metabolic and morphologic changes. After removal, some of the normal characteristics of these cells were recovered and this was reflected in transcriptomic changes present in the acute response that were not present one week after the wash-out of the rotenone. Moreover, pre-exposed cells showed different transcriptomic profiles and metabolic patterns to those that had not been exposed before, showing long-term adaptive behaviour of these cells. In summary, this study proposes a 3D in vitro neuronal model to perform toxicological studies that take into account the long-term mechanisms derived from continued exposure to toxic compounds.
Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone
Lena Smirnova
Added on: 08-31-2021
Testing the capacity of oncolytic virus to treat brain cancers in patients tissue
2018
Duke University Medical Center, Durham, USA
Pediatric brain tumors could potentially be treated by poliovirus oncolytic immunotherapy. In the present study, the researchers analysed low-grade and malignant pediatric brain tumors infected with recombinant polio: rhinovirus (PVSRIPO) and determined the expression of the poliovirus receptor as proof of infection and propagation. Also, the capacity of the infection to lower cancer cell proliferation was shown in vitro. Given a similar successful translation of PVSRIPO to treat malignant gliomas in adult and pediatric patients, future work and prospective clinical trials should explore this possibility of PVSRIPO as an immunotherapeutic approach to treating pediatric brain tumors.
Poliovirus receptor (CD155) expression in pediatric brain tumors mediates oncolysis of medulloblastoma and pleomorphic xanthoastrocytoma
Eric M. Thompson
Eric M. Thompson et al. Journal of Neuropathology & Experimental Neurology 2018 [409]
EURL ECVAM [410]
Added on: 07-29-2021
Mathematical model of amyloid beta aggreagtion
2018
Southwest Research Institute, San Antonio, USA
Aggregation of amyloid-beta peptides into oligomers and insoluble fibrils is thought to be associated with the development of Alzheimer's disease. In this study, the researchers propose a discrete mathematical model for the aggregation of amyloid-beta into toxic oligomers using chemical kinetics and population dynamics. With this model, they were able to establish the conditions to make the system equilibrium unstable and to find a formula to prevent the aggregation of amyloid-beta peptides. This model can be a powerful tool for drug designers to target amyloid-beta aggregation in neurodegeneration.
A discrete mathematical model for the aggregation of β-Amyloid
Maher A Dayeh
Added on: 08-05-2021
Multicellular organoids with blood-brain barrier for neurotoxicity screening
2018
Wake Forest School of Medicine, Winston-Salem, USA
The development of a human neurovascular organoid model is reported. The model contains the six constituent cell types found within the brain cortex: human endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes and neurons, with endothelial cells enclosing the brain parenchymal cells. Cells derived from induced pluripotent stem cell (iPSC) sources were utilized to establish potential patient-specific and disease applications. It was shown that the model can be used in toxicity assessment studies for molecules that have the potential to cross or open the blood-brain barrier. Neurotoxicity screening was assessed and a model of the blood-brain barrier during clinical ischemia was established showing physiologic responses under hypoxic conditions. Taken together, the multicellular organoid model forms a functional blood-brain barrier and may be useful not only in drug discovery of novel therapeutics but also to evaluate the ability of drug candidates to cross the blood-brain barrier.
Human cortex spheroid with a functional blood brain barrier for high-throughput neurotoxicity screening and disease modeling
Doodwell Nzou
Added on: 03-16-2022
Study of serotonin effect on immune regulation using cells from multiple sclerosis patients
2018
Federal University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
MS is a chronic and debilitating condition affecting the CNS due to an immune attack against the myelin sheath. Serotonin is a CNS neurotransmitter that plays an important role in the regulation of many physiological processes and has been found to modulate the functional profile of certain immune cells. In the present study, the researchers aimed at evaluating the ability of exogenous serotonin to modulate the T-cell behaviour of patients with MS. Serotonin could attenuate in vitro the T-cell proliferation and cytokines production using cells isolated from patients. Also, serotonin favoured the expansion of regulatory T cells (Tregs) which suppress the immune response. The effect of serotonin in upregulating Treg cells was inversely correlated with the number of active brain lesions. To conclude, the data suggest that serotonin may play a protective role in the pathogenesis of MS.
Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T-cell subsets in multiple sclerosis patients
Cleonice A. M. Bento
Added on: 10-29-2021
Theoretical model of osciallations in Parkinson's disease
2018
Chinese Academy of Sciences, Shanghai, China
Parkinson's disease is one of the most prevalent neurodegenerative disorders that commonly affects aged individuals. It is characterized by a progressive loss of dopaminergic neurons without a known trigger that reduces the dopamine levels in the striatum. However, associated phenomena have been observed in patients, like changes in oscillatory activities in the basal ganglia. Some nuclei interactions have been proposed to explain this abnormal activity, but the responsible mechanisms are unclear. Here, a model of the corticothalamic-basal ganglia mean firing rate was developed to investigate the causative mechanisms of these symptoms. The results show that changes in the properties of different nuclei can induce Parkinson's disease oscillations and different frequency bands can be observed. Additionally, the mechanisms behind these oscillations are well explained by the model and the numerical simulation results. Overall, the researchers provide new insights on the potential mechanisms that influence Parkinson's oscillations using a newly developed model that may be further used as a unifying framework to study defects in oscillations in Parkinson's disease.
The oscillatory boundary conditions of different frequency bands in Parkinson’s disease
Luonan Chen, Bing Hu
Added on: 09-24-2021
Comparative proteomic analysis of an in vitro 3D model with human brain samples
2018
Edith Nourse Rogers Memorial Veterans Hospital, Bedford, USA
Pluripotent stem cells are becoming a powerful tool to model neurodegenerative diseases. Despite this, the developed models are not well characterized, and this limits their application. In this study, a comparative proteomic analysis is done between 3D human neural spheroids and post-mortem brains from Alzheimer's disease patients. The neural spheroids are produced with human iPSC obtained from samples of human peripheral blood mononuclear cells. The results reveal that 3D neuro-spheroids from Alzheimer's patients have alterations in proteins related to axonal growth, mitochondrial function and antioxidant mechanisms. Similarly, post-mortem brains analysis shows alteration of proteins related to oxidative stress, neuroinflammation and proteins related to axonal injury. The researchers are able to show that the pathologic proteomic profiles generated in the "in vitro" model correspond to those found in post-mortem samples. Overall, this study confirms the potential of human iPSC-derived brain organoids for the study of neurodegenerative diseases and proposes a series of altered proteins that can be further studied to understand the pathophysiology of Alzheimer's disease.
Common proteomic profiles of induced pluripotent stem cell-derived three-dimensional neurons and brain tissue from Alzheimer patients
Weiming Xia
Added on: 08-19-2021
Importance of biological context in the use of nanoparticles
2018
Tehran University of Medical Sciences, Tehran, Iran
Nanoparticles have been a popular research topic in recent years for the many advantages they present in clinical applications. For example, in the context of Alzheimer's disease, they have been used to target amyloid-beta. And to test the effects of these nanoparticles on oligomerization and fibrillation processes, amyloid-beta is commonly used. However, the effects of the biomolecular corona, the biomolecules covering the surface of nanoparticles when in contact with biological fluids, on these pathological processes have been mostly ignored. In this study, the effects of the biomolecular corona derived either from human cerebrospinal fluid or plasma on amyloid-beta dynamics were investigated. The results showed that the interactions with amyloid-beta of the different biomolecular coronas triggered different outcomes of the nanoparticles in the aggregation of different amyloid-beta peptides. Plasma-derived biomolecular corona had less inhibitory effects on amyloid-beta 42 fibrillation than none or cerebrospinal fluid-originated corona, and the opposite was true for amyloid-beta 25-35 peptide. The researchers demonstrate that it is important to study the biological context where the nanoparticles will be used and the results shown here give new clues to future applications of nanoparticles and the potential profit of the environment to modulate their activity.
Biomolecular corona dictates Aβ fibrillation process
Rassoul Dinarvand
Added on: 08-27-2021
In silico screening of multi-target inhibitors for Alzheimer's disease
2018
University of Leuven, Leuven, Belgium
Alzheimer's disease is one of the most prevalent neurodegenerative diseases. One of its consequences is the dysregulation of cholinergic activity, which leads to cognitive decline. Inhibition of acetylcholinesterase is a largely used therapeutic strategy to prevent the loss of cholinergic function in Alzheimer's disease, but nowadays the field is turning to multitarget-directed ligands to affect several facets of the disease. Here, a bioinformatic approach is used to perform an "in silico" screening of potential therapeutic molecules that match these multi-target characteristics. Through a complex workflow of different discrimination steps, the researchers found four multi-target inhibitors with interesting protein-ligand stability, calculated with a new approach presented in the study. This method allows for an efficient drug screening strategy that identifies multi-target inhibitors with good ADMET profiles that have promising affinities against acetylcholinesterase and other potential hits that can be further tested in vitro for their potential clinical use.
In silico structure-based identification of novel acetylcholinesterase inhibitors against Alzheimer's disease
Muhammad Usman Mirza
Added on: 08-15-2021
Mathematical model of pathological calcium signalling in neuronal death
2018
Nanyang Technological University, Singapore, Singapore
Amyloid-beta accumulation leads to disturbed calcium signalling in neurons in Alzheimer's disease, leading to apoptosis. Here, a mathematical model is presented that combines models of amyloid deposition, calcium signalling and mitochondrial permeability transition pore-related cell apoptosis in Alzheimer's disease. Results show that without amyloid deposition, calcium levels remain at resting concentration, while in the simulated pathological situation there is an intracellular dysregulation of calcium ions and channels. This mathematical model allows the study of potential calcium-related pathological mechanisms in Alzheimer's disease that are not easily accessible experimentally.
Composite mathematical modeling of calcium signaling behind neuronal cell death in Alzheimer’s disease
Jie Zheng
Added on: 08-05-2021
Pretreatment of tissue for transplantation in Parkinson's disease
2018
University of Bern, Bern, Switzerland
Parkinson's disease is a devastating neurodegenerative disorder with no effective cure characterized by a massive loss of dopaminergic neurons that leads to motor dysfunction, cognitive decline and, ultimately, death. Recently, cell replacement therapy has attracted growing attention as a possible treatment strategy. However, low survival and suboptimal graft integration have limited its application. Here, pretreatment of fetal ventral mesencephalic tissue with neurotrophin-4/5 and glial cell line-derived neurotrophic factor is tested to improve the outcome of dopaminergic neurons transplantation. The results show that the treatment with both factors increased the number of tyrosine hydroxylase positive neurons and the dopamine content in the culture supernatant. Additionally, the cell viability was also increased after treatment. Overall, this study shows that pretreatment of donor tissue with neurotrophin-4/5 and glial cell line-derived neurotrophic factor leads to the production of dopaminergic neurons and increases cell survival, which can be a step forward towards the application of cell transplantation of dopaminergic neurons in Parkinson's disease.
A combination of NT-4/5 and GDNF is favorable for cultured human nigral neural progenitor cells
Hans R. Widmer
Added on: 09-01-2021
Tau seeding dynamics in Alzheimer's disease
2018
Harvard Medical School, Charlestown, USA
Hyperphosphorylated tau aggregates in the form of neurofibrillary tangles are a hallmark of Alzheimer's disease. Many studies have suggested a "prion-like" behaviour of tau aggregates along neurons. In this study, different tools are used to analyse tau dynamics in human models of Alzheimer's disease. First, lysates of human brain areas with scarce neurofibrillary tangles were capable of inducing substantial tau seeding in a human tau biosensor cell line. Also, tau seeding was detected in areas of the human central nervous system affected by the pathology and the non-affected containing regions, and in areas that contain little to no neuronal cell bodies. This data suggested that pathogenic tau aggregates precede tau pathology with transneuronal spread through synapses, which was confirmed by the significant enrichment of seed competent tau in synaptosome fractions isolated from brains of varying Braak stages. This study provides evidence that tau pathology might be spread along the synaptic connections and linked to the extension of Alzheimer's pathogenesis in the human brain. Further investigation on this matter might bring new potential targets to stop the spread of the disease.
Synaptic tau seeding precedes tau pathology in human Alzheimer's disease brain
Bradley T Hyman
Added on: 08-16-2021
A role of brain organoids in Parkinson's research
2018
University of Luxembourg, Belvaux, Luxembourg
This review presents the hypothesis that Parkinson's disease (PD) is a neurodevelopmental disorder and discusses the role of modern stem cell technologies, including the generation of personalized brain organoids, in PD therapy and drug development
Is Parkinson's disease a neurodevelopmental disorder and will brain organoids help us to understand it?
Jens C. Schwamborn
Added on: 05-25-2020
Computational study of inflammatory pathways in neurodegeneration
2018
University of Luxembourg, Luxembourg, Luxembourg
An analysis of post-mortem brains affected by Alzheimer's disease has shown a clear involvement of inflammation in the pathology of the disease. Here, a new computational approach is used to study six neuronal populations from Alzheimer's patients. The goal of this method is to identify signalling pathways that might be activated or inhibited during the pathology progress and which result in neurotoxicity. With this method, the researchers were able to describe several altered inflammatory mediators, with a considerable amount of region-specificity among them. In summary, this computational method could identify inflammatory pathways that may have a key role in the development of Alzheimer's disease and can be a powerful tool to translate omics data into therapeutical approaches.
Integrative computational network analysis reveals site-specific mediators of inflammation in Alzheimer's disease
Antonio Del Sol
Added on: 08-06-2021
CXCR4 as a target for aging and Alzheimer's disease
2018
Capital Medical University, Beijing, China
Alzheimer's disease is one of the most prevalent neurodegenerative disorders. Ageing is a major factor in the development of spontaneous Alzheimer's disease and is characterized by a progressive deterioration of brain homeostasis and function. Here, the role of the G-protein coupled receptor CXCR4 in ageing and Alzheimer's disease is investigated, since a reduction in its levels is present in Alzheimer's disease and it has been linked to developmental processes and synaptic plasticity. The results show that CXCR4 is necessary for cell proliferation and its knock-down induces cytotoxicity in human neural cells. Also, a potential signalling pathway is described, through which CXCR4 activation may work. Overall, this study suggests CXCR4 as a potential novel target to study ageing and Alzheimer's disease and offers mechanistic insights into its regulatory functions, which could lead to new approaches in therapeutic strategies.
Reducing CXCR4 resulted in impairing proliferation and promoting aging
Rong Wang
Added on: 08-22-2021
DNA methylation-based tumor classification
2018
Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany, Heidelberg, Germany(1)
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany(2)
Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany(2)
A big biobank consisting of patient-derived central nervous system tumor biopsies is being developed and utilized for the establishment of a DNA methylation-based tumor classification (https://www.molecularneuropathology.org/mnp). An integrated online tool allows researchers to upload their methylome data, which is then automatically compared to methylation data of a reference cohort comprising over 2800 neuropathological tumors.
MolecularNeuropathology.org - The platform for next generation neuropathology
Andreas von Deimling(1), Stefan Pfister(2)
Added on: 04-21-2020
Immunofluorescence in brain cancer tissues to reveal potential for immune checkpoint inhibitors treatment
2018
Brigham and Women’s Hospital, Boston, USA
Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. In the present study, the researchers explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in craniopharyngiomas. The researchers mapped and quantified PD-L1 and PD-1 expression in patients' resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. Also, they used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signalling pathways in tumor cells that intrinsically express PD-1. All results indicate that targeting PD-L1 and/or PD-1 in craniopharyngioma might be an effective therapeutic strategy.
Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma
Sandro Santagata
Added on: 07-29-2021
Interactions between blood vessel and spinal neuronal tissues on-a-chip
Company 2018
Cedars-Sinai Medical Center, Los Angeles, USA(1)
Emulate Inc., Boston, USA(2)
Emulate Inc., Boston, USA(2)
The researchers used an organ-on-a-chip model to study the interaction between human blood vessel tissue and spinal cord tissue derived from human stem cells (iPSCs). They discovered that the blood vessel tissue can activate genes to direct the development and maturation of spinal cord tissue. The study not only offers insights into how spinal cord tissues develop, it also offers an experimental model to study diseases affected by defects in motion-controlling brain cells, such as amyotrophic lateral sclerosis (ALS).
Human iPSC-derived endothelial cells and microengineered Organ-Chip enhance neuronal development
Clive N. Svendsen(1), Samuel Sances(1), (2)
Added on: 05-25-2020
Identification of metabolic biomarkers of Alzheimer's disease
2018
National Institutes of Health (NIH), Baltimore, USA
Alzheimer disease is a multifactorial neurodegenerative disease that leads to cognitive decline and death. Despite the accumulating knowledge, the relationships between metabolic perturbations and Alzheimer's pathogenesis are poorly understood. Thus, new insights into the global perturbations in metabolism caused by or that lead to Alzheimer's disease are critical to develop better therapeutic strategies. Here, a parallel metabolic analysis of brain and blood samples from different cohort studies were performed to identify alterations that correlate the development of the pathology to the prodromal and preclinical measures of Alzheimer's progression. With machine learning, it was possible to elucidate 26 metabolites in brain samples that effectively discriminated between healthy and diseased patients. The same metabolites were analysed in blood samples to correlate them with various tests performed during the cohort studies and were found to be consistently associated with Alzheimer's severity at autopsy and Alzheimer's progression. The biological pathways to which the metabolites were related included several already known pathways relevant to Alzheimer's disease. In this study, the researchers identify a group of metabolites from blood and brain samples as potential biomarkers of Alzheimer's severity and progression that could also open the door to new therapeutical targets to tackle metabolism perturbations in the disease.
Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study
Madhav Thambisetty
Added on: 10-01-2021
In vitro assay based on human cells to demonstrate increased migration capacity of therapeutic immune cells
2018
University of Antwerp, Wilrijk, Belgium
Multiple sclerosis (MS) is a chronic autoinflammatory disease of the central nervous system. Although tolerance-inducing dendritic cells (tolDCs) have been shown to be promising therapeutics to control the inflammation process, the clinical use of these cells depends largely on their capacity to migrate and reach target organs. In the present study, the researchers increased the migration capacity of dendritic cells by overexpressing one particular gene involved in migration and demonstrated it in an in vitro model of the blood-brain barrier (BBB). Dendritic cells were prepared from blood obtained from healthy donors, the blood-brain barrier model was constructed by co-culturing human cells in different layers. The approach used herein has important implications for the treatment of MS. Using this approach, tolDCs actively shuttle across the BBB, allowing in situ down-modulation of autoimmune responses in the CNS.
Shuttling tolerogenic dendritic cells across the blood–brain barrier in vitro via the introduction of de novo C–C chemokine receptor 5 expression using messenger RNA electroporation
Nathalie Cools
Added on: 09-20-2021
Model of the brain network
2018
Charité – Universitätsmedizin Berlin, Berlin, Germany
On a platform called "The Virtual Brain", individual patient brain measurements are evaluated and personalized models are created that simulate the characteristics of the patient's brain activity. The tool allows researchers to evaluate the neural interactions involved and enables the patient's data to be used to predict neural network interactions. Unlike other computer models, this mathematical platform can process real-time human data to make better predictions about brain processes that are relevant to each individual patient and thus enables personalized medicines. In this way, individual differences in brain functions and underlying mechanisms of brain diseases can be uncovered.
Inferring multi-scale neural mechanisms with brain network modelling
Petra Ritter
Added on: 05-25-2020
Mortalin is a potential biomarker for Parkinson's disease
2018
All India Institute of Medical Sciences, New Delhi, India
Parkinson's disease is one of the most prevalent neurodegenerative disorders. It is characterized by a progressive loss of dopaminergic neurons that leads to motor and cognitive decline and, ultimately, death. The accumulation of alpha-synuclein is a hallmark of the disease and, in some cases, it accumulates in structures called Lewy bodies. Mortalin reduces Lewy bodies toxicity and it has been shown to be downregulated in brain tissue samples of Parkinson's patients. In this study, the correlation of Mortalin and alpha-synuclein has been assessed in serum of Parkinson's patients using surface plasmon resonance. The results showed that Mortalin levels are lower in Parkinson's patients, contrary to alpha-synuclein, which was elevated in these same samples. Further statistical analysis confirmed the negative correlation between these two factors in samples from patients with Parkinson's disease. Overall, the researchers confirmed that Mortalin correlates with alpha-synuclein levels, making it a potential easily accessible serum biomarker for the diagnosis and monitoring of Parkinson's disease.
Serum Mortalin correlated with α-synuclein as serum markers in Parkinson’s disease: a pilot study
Sharmistha Dey
Added on: 09-10-2021
Sample preconcentration to increase sensitivity of amyloid-beta peptides detection
2018
Université Paris-Sud, Chatenay-Malabry, France
Detection of amyloid-beta peptides in the cerebrospinal fluid of patients has been used as a tool to diagnose and follow the development of Alzheimer's disease. However, the efficacy of the existing tools is limited and the capabilities to detect low concentrations and different amyloid-beta peptides are not well developed. Here, a new approach is developed to concentrate the samples and achieve sensitive and simultaneous detection of different amyloid-beta peptides to be used as biomarkers for diagnostic purposes. This electrokinetic system was able to detect subnanomolar ranges of amyloid-beta 38, 40 and 42 in the cerebrospinal fluid of Alzheimer's patients and non-demented controls. The quantification limits of this system coupled to a laser-induced fluorescence detection were 0.05nM, which represents up to 170 times more sensitivity. The researchers present a new tool that can have a great clinical potential to improve the detection of amyloid-beta peptides at very low concentrations, making it easy to track the onset of the disease, without the need of using immune techniques or other complicated approaches.
Online preconcentration in capillaries by multiple large-volume sample stacking: An alternative to immunoassays for quantification of amyloid beta peptides biomarkers in cerebrospinal fluid
Myriam Taverna
Added on: 08-28-2021
Tranylcypromine causes neurotoxicity and represses BHC110/LSD1 in human cerebral organoids
December 2017
Central South University (CSU), Changsha, China
Recent breakthroughs in human pluripotent stem cell-derived cerebral organoids provide a valuable platform for investigating the human brain after different drugs treatments and for understanding the complex genetic background to human pathology. The authors of this study identified tranylcypromine, which is used to treat refractory depression, caused human-induced pluripotent stem cell-derived brain organoids neurotoxicity, leading to decreased proliferation activity and apoptosis induction. Moreover, tranylcypromine treatment affected neurons and astrocytes, which impaired cell density and arrangement.
Finally, staining of histone demethylation-related genes revealed that tranylcypromine suppresses the transcriptional activity of BHC110/LSD1-targeted genes and increased the expression of histone di-methylated K4. These results show that human brain organoids can be applied as an in vitro model for CNS drug screening to evaluate structural, cellular, and molecular changes in the normal brains or brains of patients with neuropsychiatric disorders after drug treatments.
Tranylcypromine causes neurotoxicity and represses BHC110/LSD1 in human-induced pluripotent stem cell-derived cerebral organoids model
Jindong Chen
Added on: 05-09-2023
CRISPR manipulated human fibroblasts as a model for Alzheimer's disease
November 2017
Columbia University Medical Center, New York, USA
Alzheimer's disease main causative hypothesis in the last years is the amyloid hypothesis: several alterations in the processing of amyloid precursor protein lead to an accumulation of amyloid-beta that results in brain degeneration. Some of these alterations in the familial version are related to gene mutations considered as risk factors. Two of them are mutations in the presenilin 1 and 2 genes, components of the gamma-secretase complex that produces amyloid-beta. In this study, an in vitro model based on human skin fibroblasts from familial Alzheimer's disease patients is used to study the effect of the activation of endogenous genes related to the disease. Through CRISPR manipulation, the researchers describe that the activation of amyloid precursor protein and/or beta-secretase genes shows a defective cleavage of gamma-secretase that leads to amyloid-beta 42 accumulation. Here, an easy-to-obtain and -use model described that can help to uncover pathogenic mechanisms through controlled manipulation of specific genes directly in patient samples.
CRISPR transcriptional activation analysis unmasks an occult g-secretase processivity defect in familial Alzheimer’s disease skin fibroblasts
Asa Abeliovich, Keiichi Inoue
Added on: 08-20-2021
Effect of amyloid beta in choline metabolism
November 2017
University of Western Ontario, London, Canada
The impaired function of cholinergic neurons is a main factor in Alzheimer's disease-related cognitive decline. Deficits in the normal homeostasis of high-affinity choline transporter lead to impaired cholinergic neurotransmission due to disturbed choline homeostasis. Amyloid beta, an important driver of Alzheimer's pathology, has been shown to impair normal synaptic transmission. Here, the role of amyloid-beta peptides on choline metabolism is studied using a human neuroblastoma cell line. The researchers show that amyloid-beta decreases choline uptake and reduces the amount of high-affinity choline transporter on the cell membrane through disruption of its normal recycling. Lysosomal inhibition could counteract this effect but did not avoid amyloid-beta effects on the transporter's activity. Finally, the researchers could ameliorate the pathological phenotype with the use of antibodies directed to the mid-region of amyloid-beta peptide, indicating a specific epitope or conformation responsible for this behaviour. Overall, this study reveals valuable mechanistic insights into amyloid beta's disruption of choline homeostasis in a human model that can be potentially used in further studies to better direct the therapeutic strategies towards more effective targets.
Amino-terminal β-amyloid antibody blocks β-amyloid-mediated inhibition of the high-affinity choline transporter CHT
R Jane Rylett
Added on: 08-17-2021
New assay to study peptide aggregation
November 2017
University of Central Florida, Orlando, USA
Accumulation of alpha-synuclein is a hallmark of Parkinson's disease, a highly prevalent neurodegenerative disorder. However, the dynamics of the endogenous form in the human brain are not well-understood because of the lack of samples to study and reliable methods to analyze them. In this study, a single-molecule pull-down assay combined with in vivo crosslinking is used to study alpha-synuclein in postmortem human brains. The results showed that this technique can be successfully used to study alpha-synuclein at the single-molecule level using minimum amounts of protein and that it can be used to study the oligomerization states in human cultured cells and postmortem human brain samples. Overall, the researchers propose a new powerful tool that has the potential to be used to diagnose Parkinson's disease and other diseases that involve the accumulation, oligomerization and aggregation of specific peptides.
Endogenous alpha-synuclein protein analysis from human brain tissues using single-molecule pull-down assay
Yoon-Seong Kim, Kyu Young Han
Added on: 09-10-2021
Therapeutic effects of an amyloid beta antibody fragment
November 2017
Universitat Autònoma de Barcelona, Barcelona, Spain(1)
VU University Medical Center, Amsterdam, Netherlands(2)
VU University Medical Center, Amsterdam, Netherlands(2)
Amyloid-beta-induced cytotoxicity is one of the main pathological features of Alzheimer's disease. Immunotherapy against amyloid-beta peptides and/or aggregates has been intensively studied during the last years with certain success. However, little is known about the effects that other molecules involved in the development of the disease have on the therapeutical performance of the anti-amyloid beta antibodies. A recently published study showed an anti-amyloid beta antibody fragment that restored normal values of apolipoprotein E and J and reduced amyloid beta internalization by glial cells. Here, with the use of mimetic peptides of these apolipoproteins, the effect of the therapeutic antibody is tested on amyloid-beta aggregation and cellular uptake by primary human astrocytes. The results show that apolipoprotein E induced conformational changes and interfered with the reduction of astrocytic amyloid-beta uptake induced by the antibody. Meanwhile, apolipoprotein J seemed to induce the formation of protective fibrils in coordination with the antibody and did not interfere with the uptake of amyloid-beta by astrocytes induced by the antibody fragment. Overall, the researchers state that both lipoproteins and the antibody reduce the astrocytic uptake of amyloid-beta, although through different mechanisms, which could reduce astrocyte malfunction and ultimately increase neuronal viability. Therefore, this study opens the door to continue investigating an anti-amyloid beta antibody fragment that could affect different therapeutic targets at the same time.
Effects of an Aβ-antibody fragment on Aβ aggregation and astrocytic uptake are modulated by apolipoprotein E and J mimetic peptides
Sandra Villegas(1), Robert Veerhuis(2)
Added on: 08-19-2021
A mathematical model of different multiple sclerosis variants
October 2017
University of Barcelona, Barcelona, Spain
The authors developed a mathematical model to simulate the biological processes involved in the progression of multiple sclerosis (MS) by evaluating patient data from 20 years. The results of this model were supported by pathological findings and suggested a common pathogenesis for the different MS subtypes, leading to a variety of clinical outcomes in different patient groups. This model is more meaningful to humans than animal experiments because it can predict different disease courses in patients.
Dynamics and heterogeneity of brain damage in multiple sclerosis
Pablo Villoslada
Added on: 05-25-2020
Acetylcholine protects agains amyloid-beta toxicity
October 2017
Institute of Diagnosis and Treatment Hermitage, Naples, Italy
The amyloid hypothesis has been the most accepted causative theory of Alzheimer's disease during the last decades. Amyloid-beta aggregation is considered a main pathological process and is responsible for neuronal loss and function impairment. In recent studies, it has been shown that acetylcholine can act as a neuroprotective agent against amyloid-beta toxicity by promoting conformational changes in the peptide. Here, the effect of acetylcholine on amyloid-beta mediated phosphorylation of the cytosolic phospholipase A2 is investigated in a human neuroectodermal cell line. The results show that these cells are responsive to amyloid-beta and that, in undifferentiated cells, it induces a 2.5-fold increase of cytosolic phospholipase A2 phosphorylation, but not in long-term treatments. Moreover, acetylcholine treatment on these cells was able to disrupt amyloid-beta effects. Overall, this study reinforces the idea that acetylcholine can have neuroprotective effects on non-cholinergic cells and opens the door to new therapeutic strategies against amyloid-beta mediated toxicity.
Effects of acetylcholine on β-amyloid-induced cPLA2 activation in the TB neuroectodermal cell line: implications for the pathogenesis of Alzheimer’s disease
Giuseppe Sorrentino
Added on: 08-22-2021
Amyloid beta transport through an in vitro blood-brain barrier
October 2017
University of British Columbia, Vancouver, Canada
Amyloid-beta accumulation in the brain is one of the hallmarks of Alzheimer's disease. Defective clearance of amyloid-beta through the blood-brain barrier causes cerebral amyloid angiopathy and is present in most Alzheimer's disease patients. Here, a 3D bioengineered human vessels model is used to study amyloid-beta clearance through cerebrovascular microvessels. This model consists of a scaffold seeded with human endothelial cells and human smooth muscle cells in the presence or not of human astrocytes and is located in a chamber connected to a microfluidic system. In this setup, the researchers show that brain and circulating lipoproteins synergise to clear amyloid-beta across the modelled human vessels. However, these mechanisms show differences depending on the amyloid-beta peptide and the brain lipoprotein isoforms, corresponding to what is observed in human patients. The results show that this newly developed model can reflect the complexity of the cerebrovascular environment and give new insights into the pathological processes that occur during neurodegenerative diseases involving the vascular system in a human context.
Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels
Cheryl L Wellington, Jerome Robert
Added on: 08-18-2021
Amyloid-beta neurotoxicity mechanisms tested in vitro
October 2017
Tallinn University of Technology, Tallinn, Estonia
Several studies support that Alzheimer's disease onset is related to the accumulation of amyloid-beta in the brain. However, the mechanisms by which amyloid aggregates lead to neuronal degeneration are still unknown. Here, a human neuroblastoma cell line is used to study the cytotoxicity of amyloid-beta peptides. Comparing differentiated and non-differentiated cells, the researchers show that the first are more sensitive to amyloid peptides, due to having longer neurites. Soluble amyloid-beta 1-42 is shown to cover cell bodies and neurites in differentiated cells, causing neurite degeneration. When using preformed amyloid fibrils, it was not possible to reproduce the toxicity of the peptide, which was complemented with the fact that spontaneously fibrillizing amyloid-beta 1-42 was more toxic than amyloid-beta 1-40, which did not form fibrils. The results elucidate important aspects of amyloid aggregates-induced neurotoxicity that could help to better understand the pathophysiology of Alzheimer's disease.
In situ fibrillizing amyloid-beta 1-42 induces neurite degeneration and apoptosis of differentiated SH-SY5Y cells
Jekaterina Krishtal
Added on: 08-17-2021
Amyloid-beta oligomerization dynamics
October 2017
University of California, Davis, USA
The amyloid-beta peptide in its oligomeric form is a major pathogenic element in the development of Alzheimer's disease. In this study, the researchers aim to quantify the binding of pyrroline-nitroxyl fluorene, an amyloid-beta toxicity blocker, and its effect on the peptide. The results show that the binding affinity depends on the oligomeric state of amyloid-beta, being easier to be bound when it is in its monomer or dimer form compared to its oligomeric forms. To further understand the dynamics of these interactions, a molecular dynamics simulation is used together with molecular docking to define conformational states that correlate to lower toxicity and aggregation propensity of amyloid-beta. This study brings new mechanistic insights of pharmaceutical relevance and develops a methodology to increase the "in vivo" relevance of the results, providing a platform to investigate the potential modulation of peptide aggregation as a therapeutic target in other disorders.
Oligomerization alters binding affinity between amyloid beta and a modulator of peptide aggregation
John C Voss
Added on: 08-10-2021
Changes in the proteome of human cerebral organoids induced by 5-MeO-DMT
October 2017
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Dimethyltryptamines are entheogenic serotonin-like molecules present in traditional Amerindian medicine recently associated with cognitive gains, antidepressant effects, and changes in brain areas related to attention. Legal restrictions and the lack of adequate models have limited the understanding of how such substances impact human brain metabolism. Here a shotgun mass spectrometry was used to explore proteomic differences induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico analysis reinforced previously reported anti-inflammatory actions of 5-MeO-DMT and revealed modulatory effects on proteins associated with long-term potentiation, the formation of dendritic spines, including those involved in cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization. The presented data offer the first insight about molecular alterations caused by 5-MeO-DMT in human cerebral organoids.
Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT
Stevens K. Rehen
Added on: 05-09-2023
Computational model of amyloid-beta aggregation
October 2017
Rice University, Houston, USA(1)
University of Miami, Coral Gables, USA(2)
University of Miami, Coral Gables, USA(2)
Currently, the onset of Alzheimer's disease is thought to be linked to the transition of amyloid-beta from soluble peptides to aggregated fibrils. Therefore, inhibiting amyloid-beta aggregation has been a long-pursued objective. But how amyloid-beta aggregates and how different molecules bind to it is still not known. Here, a rhenium complex that binds to amyloid-beta is used to identify its binding sites through light irradiation. Afterwards, the researchers used molecular dynamics to simulate the binding sites of amyloid-beta with the rhenium complex. The identified locations were further confirmed by the identification of oxidised sites via tandem mass spectrometry. This method elucidates binding sites and mechanisms that could be potentially used to design therapeutic strategies to interrupt amyloid-beta aggregation and/or accumulation.
Photochemical identification of molecular binding sites on the surface of amyloid-β fibrillar aggregates
Angel A Martí(1), Rajeev Prabhakar(2)
Added on: 08-09-2021
Effects of cortical activity on medium sized spiny neurons in dopamine-depleted contexts
October 2017
South China University of Technology, Guangzhou, China
Parkinson's disease is a major neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons that innervate the striatum. There is evidence that the overexposure of medium-sized spiny neurons to cortical glutamatergic input induces a loss of dendritic spines and dendritic length, proposed as a mechanism to protect these neurons from excess excitatory inputs. However, there is a lack of consistency in the degeneration of dendritic components in medium-sized spiny neurons in experimental conditions. To solve this, the researchers propose a computational model to investigate the amount of dendritic spines and dendritic arborization loss to restore the normal regulatory function of the basal ganglia. The results showed that dendritic spine loss and/or dendritic trees could restore normal activity in specific dopamine level conditions through different mechanisms. Furthermore, the model allowed to explore the effects of cortical activity on the morphology of medium-sized spiny neurons in dopamine-depleted conditions and it elucidated that the manipulation of cortical activity can stop the degeneration of dendrites. In this study, a new updated model is developed to propose a potential therapeutical strategy through the manipulation of cortical inputs into medium-sized spiny neurons in Parkinson's disease and dopamine depletion context to stop dendritic degeneration.
The effects of medium spiny neuron morphologcial changes on basal ganglia network under external electric field: a computational modeling study
Shenquan Liu
Added on: 09-30-2021
Metabolic changes in vitro after protein aggregates challenge
October 2017
University of Liverpool, Liverpool, United Kingdom
Protein aggregation is a pathogenic process present in several neurodegenerative diseases. However, the aggregation states and their effects on cellular viability are unclear. Here, a method is developed to perform metabolomics using nuclear magnetic resonance to study the effects of different protein aggregates in a human neuroblastoma cell line. The results elucidate key metabolites related to different pathways that are altered in this cell line when challenged with different aggregated forms. Furthermore, the system is capable of suggesting different cellular behaviours for different aggregated forms. Monomer or oligomeric forms induce a cellular response against oxidative stress, while metabolic changes in fibrillar challenge are less prevalent but indicate a more toxic response driving to cytotoxicity. The researchers present a methodology that can be used to systematically study potentially toxic insults in different cell types to build metabolic profiles. This represents a potential step forward towards the identification of target and therapeutic strategies to alleviate the toxicity of protein aggregation in different neurodegenerative diseases.
Using an NMR metabolomics approach to investigate the pathogenicity of amyloid-beta and alpha-synuclein
Jillian Madine
Added on: 08-17-2021
Computational approach to study protein structural properties and transformations
2017
Southern Medical University, Guangzhou, China
Alpha-synuclein is a protein with a significant role in several diseases known as synucleinopathies. Its dimerization can trigger conformational transformations critical for its aggregation and the formation of fibrils. In this study, molecular dynamics simulations are used to investigate the mechanisms of dimerization of alpha-synuclein and its structural properties. The results show that, effectively, the monomers undergo a series of conformational transformations and they can resolve several structural features that are consistent with current experimental observations. These transformations lead to intermolecular interactions that contribute to the formation and stabilization of alpha-synuclein dimers. The researchers present a computational strategy that can help to design small molecules that can inhibit the pathological processes that lead to alpha-synuclein aggregation.
Molecular dynamics study to investigate the dimeric structure of the full-length α-synuclein in aqueous solution
Jiajie Zhang, Shuwen Liu
Added on: 08-10-2021
Computational simulations to decipher drug properties
2017
Sharif University of Technology, Tehran, Iran
Aggregation of amyloid-beta is one of the main hallmarks of Alzheimer's disease. Different strategies are being investigated to inhibit its polymerization and/or avoid amyloid formation. Here, molecular dynamics is used to elucidate the interactions of RS-0406 with different amyloid-beta polymers. RS-0406, a small organic molecule, has already shown promising results in inhibiting amyloid formation in vitro. Using experimental and computational log P values, the researchers are able to describe different mechanisms by which RS-0406 affects the conformational stability of the polymers. They found that it affects both the stabilization of monomers and the destabilization of fibril structures. In summary, with this method, it is possible to describe the unique structural features from this small molecule that affect the amyloid formation and the mechanisms behind its effect. This platform could be used to investigate drug-related properties and drug interactions with protein structures to better understand their mechanisms and design better therapeutic strategies.
Inhibition mechanisms of a pyridazine-based amyloid inhibitor: as a β-sheet destabilizer and a helix bridge maker
Hamid R Kalhor
Added on: 08-10-2021
Mechanisms of dopaminergic differentiation in vitro
2017
Xuzhou Medical University, Xuzhou, China
Parkinson's disease is a neurodegenerative disorder characterized by a massive loss of dopaminergic neurons. Several pharmacological strategies are used to alleviate the symptoms of the disease, but there is not yet an effective cure for the disease. Recently, cell replacement therapy is growing in popularity as a potential strategy for dopaminergic regeneration in Parkinson's disease. However, the mechanisms of differentiation of dopaminergic neurons are not well-known. Here, a human neuroblastoma cell line treated with glial cell-derived neurotrophic factor is used to elucidate key factors in the differentiation of dopaminergic neurons, with a special focus on glucose-6-phosphatase. Firstly, the researchers defined the conditions for glial cell-derived neurotrophic factor treatment for the differentiation process. Afterwards, it was confirmed that glucose-6-phosphatase expression is significantly upregulated throughout the differentiation and propose three microRNAs as key factors in this process. These results could be confirmed at a protein level. Overall, in this study, glucose-6-phosphatase is validated as an important factor in dopaminergic differentiation from a human neuroblastoma cell line, which might contribute to the investigation of dopaminergic cells production for cell-based therapies in Parkinson's disease.
Glucose-6-phosphatase-α participates in dopaminergic differentiation
Dian-Shuai Gao
Added on: 09-02-2021
Role of a cytokine in Vogt-Koyanagi-Harada disease determined using patients' immune cells
2017
The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disease that usually causes bilateral granulomatous panuveitis and results in decreased visual acuity. If not treated in a timely manner, this disease can lead to blindness. In the present study, the researchers aimed at uncovering if cytokine IL-9, which is involved in various autoimmune diseases, could also be involved in VKH. The researchers isolated immune cells from VKH patients and cultured them in vitro. The expression of a repertoire of cytokines was tested in the primary cells, and IL-9 mRNA levels were higher in VKH individuals than in control. The secretion of cytokines that were present in the culture supernatant was investigated and IL-9 levels were higher in VKH than in control. Finally, exposure to supplemental doses of IL-9 was assessed and showed no increase of proliferation but an increase in the secretion of pro-inflammatory cytokine IL-17. In conclusion, the data show the involvement of IL-9 with the disease and suggest that manipulation of IL-9 might represent a novel option for the treatment of VKH disease.
Expression and role of interleukin-9 in Vogt-Koyanagi-Harada disease
Qian Wang
Added on: 10-31-2021
Role of regulatory T cells in myasthenia gravis studied using patients' cells
2017
Istanbul University, Istanbul, Turkey
Myasthenia gravis (MG) is the most common humoral and cellular immune-mediated neuromuscular disorder, caused by autoantibodies against the acetylcholine receptor of skeletal muscles. Regulatory T cells (Treg) are an essential component in the counterbalance of the autoimmune response by regulating the activation, proliferation and cytokine production of autoreactive cells. In the present study, the researchers aimed at investigating cytokine-related mechanisms that may lead to the defect of Treg in patients with MG. T cells were isolated from patients and tested in vitro for their capacity for suppression of immune response. The results show an impaired immune regulation in patients with MG which is associated with changes in cytokine production. The findings suggest that MG should be considered among candidate diseases for cytokine-based immunotherapy approaches.
The effect of interleukin (IL)-21 and CD4+CD25++ T cells on cytokine production of CD4+ responder T cells in patients with myasthenia gravis
G. Saruhan-Direskeneli
Added on: 10-29-2021
Oxidative stress mechanisms in a human iPSC neural model
2017
Joint Research Centre, Ispra, Italy
Advances in the manipulation of human pluripotent stem cells are opening the door to their use for toxicity in vitro modelling. Since the appearance of iPSC technology, human iPSC-derived brain cells have been used for compound neurotoxicity testing. In these cells, it has been shown that the Nrf2/ARE pathway is activated under oxidative stress conditions. Rotenone is widely used as an oxidative stress activator and is usually used to assess neurotoxicity. Here, the effects of chronic exposure to rotenone on human iPSC-derived neural stem cells along differentiation are investigated, focusing on the Nrf2 pathway. The researchers found that Nrf2 signalling increases during neural stem cell differentiation. The addition of rotenone induced a progressive increase of Nrf2 signalling, together with astrocyte reactivity and neurite retraction that lead to neuronal death, especially of dopaminergic neurons. Overall, in this study, human iPSC-derived neural cells are validated as a powerful tool to elucidate the role and mechanisms of different signalling pathways in neurodevelopment upon treatment with potential neurotoxic compounds.
Nrf2 pathway activation upon rotenone treatment in human iPSC-derived neural stem cells undergoing differentiation towards neurons and astrocytes
Anna Bal-Price
Added on: 09-03-2021
Endothelial disruption by challenged astrocytes
2017
University of Catania, Catania, Italy
The integrity of the blood-brain barrier is essential for normal brain homeostasis. However, it can be easily disrupted if any of its cellular components is altered. This is the case in several pathologies, like Alzheimer's disease. In this study, an in vitro blood-brain barrier human model is used to study the interaction between human endothelial cells and human astrocytes after exposure to amyloid-beta. In co-culture conditions, the exposure to amyloid-beta 1-42 induced the dysfunction of endothelial cells in a permeability assay, contrary to when endothelial cells are cultured alone. Furthermore, the disruption of endothelial cells could be reproduced with conditioned media of astrocytes exposed to amyloid-beta. The researchers found out that this was a consequence of the increased activity of matrix metalloprotease 9 mediated by astrocytic vascular endothelial growth factor. Overall, the results elucidate a key mechanism involved in endothelial malfunction driven by challenged astrocytes exposed to amyloid-beta in a human model. This knowledge could be a great advance to understand the degradation of the blood-brain barrier in Alzheimer's disease and to develop new therapeutical strategies to target this pathology.
Astrocytes contribute to Aβ-induced blood–brain barrier damage through activation of endothelial MMP9
Maria Angela Sortino
Added on: 08-17-2021
New microRNA biomarkers for Parkinson's disease
2017
Affiliated Institute of the University of Lübeck, Bolzano, Italy
Parkinson's disease is a highly prevalent neurodegenerative disorder characterized by the massive loss of dopaminergic neurons, which leads to motor and cognitive dysfunction and, ultimately, death. Currently, there is a lack of biomarkers and early diagnostic tools for this disease. MicroRNAs have been shown to be dysregulated in several pathologies, including Parkinson's disease. Here, the microRNA profiles of plasma and white blood cells of L-dopa treated and non-treated patients are investigated to assess if they are interchangeable biomarker sources for early detection of Parkinson's disease. The results showed that the microRNA profiles of the two groups of patients have differences. Moreover, the expression profiles of plasma and white blood cells were also different. The analysis showed that miR-30a-5p could be a potential biomarker in plasma samples of Parkinson's patients, and an in silico analysis suggested that it is related to mitochondrial function and autophagy. Overall, this study proposes a new microRNA marker that could potentially develop into a new biomarker for the diagnosis of Parkinson's disease and reveals that plasma and white blood cells are not interchangeable for the analysis of biomarkers. Additional studies are needed to understand the modulation of miR-30a-5p in Parkinson's disease and how L-dopa treatment can influence microRNA expression profiles.
Plasma and white blood cells show different miRNA expression profiles in Parkinson’s disease
Luisa Foco, Christine Schwienbacher
Added on: 09-11-2021
Anti-inflammatory effects of memantine in vasuclar endothelial cells
2017
The First Affiliated Hospital of Kunming Medical University, Kunming, China
In recent years, vascular endothelium dysregulation has been related to Alzheimer's disease. Memantine is an approved drug used to treat Alzheimer's disease, but little is known about its anti-inflammatory effects on the vascular endothelium. Here, a model based on primary human brain microvascular endothelial cells triggered with tumor necrosis factor-alpha is used to study the effects of memantine on endothelial inflammation. First, memantine prevented the attachment of human monocytes to endothelial cells. Afterwards, in an insert-based blood-brain barrier model, memantine preserved the integrity of the model and inhibited monocyte transmigration through the endothelial layer. The results show that memantine was able to prevent the expression of tumor necrosis factor-alpha triggered factors by inducing the inhibition of factor NF-kB. This study deciphers the anti-inflammatory mechanisms of memantine in endothelial cells and describes an "in vitro" model of the blood-brain barrier that can be potentially used to design new therapeutical strategies for neurological disorders.
Regulation of human brain microvascular endothelial cell adhesion and barrier functions by memantine
Fei Wang
Added on: 08-16-2021
Human midbrain organoids
2017
University of Luxembourg, Esch-sur-Alzette, Luxembourg
The authors developed a robust human brain organoid system that is highly specific to the midbrain derived from regionally patterned neuroepithelial stem cells. Spatially organized groups of dopaminergic neurons, make this model suitable for Parkinson’s disease modelling and therapy development. The midbrain organoids are characterized in for neuronal, astroglial, and oligodendrocyte differentiation, the presence of synaptic connections, electrophysiological activity, and myelination of neurites.
Derivation of human midbrain-specific organoids from neuroepithelial stem cells.
Jens C. Schwamborn
Added on: 05-25-2020
Mathematical prediction of neurodegenerative disease' progression
2017
University of Western Australia, Crawley, Australia
One of the limitations of epidemiological studies is the lack of long-term data of longitudinal studies. To overcome this problem, this study presents a mathematical model to infer the underlying long-term trajectories of short-term sparse follow-up data from Alzheimer's disease studies. Through a step-wise method, the researchers are able to build a model that can reliably predict the disease progression curve, allowing them to build the sigmoidal trajectories of the disease. As a demonstration, throughout the study, they were able to quantify the long-term progression of the pathogenesis of amyloid-beta burden in the neocortex with the data from the Alzheimer's Disease Neuroimaging Initiative. In summary, this predictor model will be helpful to overcome the limitations of epidemiological studies in which participants' data collection has been abruptly interrupted and make it possible to quantify and understand full disease progression predicting long-term epidemiological data of neurodegenerative diseases.
Constructing longitudinal disease progression curves using sparse, short-term individual data with an application to Alzheimer's disease
C A Budgeon
Added on: 08-04-2021
Static electrical field affects amyloid beta aggregation
2017
Xidian University, Xi’an, China
Alzheimer's disease is the most prevalent neurodegenerative disorder. It is characterized by a progressive accumulation of amyloid beta peptides through aggregation, which has been thought to be a causal mechanism of the disease. Amyloid beta aggregation has been observed to depend on several factors, thus it is a very complex process to study. Here, a theoretical model is used to study the impact of a static electric field present in the human brain on the conformation of the amyloid beta 29-42 dimer. The simulations performed suggested that the electric field promoted the formation of beta-hairpins, an intermediate form thought to be important for the aggregation. Furthermore, the results showed that the application of different electrical field forces can help to reduce the conformational heterogeneity of amyloid beta 40/42 dimers to more easily elucidate insights into their structures that could have an influence on disease-related mechanisms. Overall, this study provides theoretical support to further explore the structural features of amyloid beta aggregates and further experiments combining different factors that can affect amyloid beta structure.
Small static electric field strength promotes aggregation-prone structures in amyloid-β(29-42)
Yan Lu
Added on: 09-30-2021
Computational model of the basal ganglia
2017
University of Sheffield, Sheffield, United Kingdom
Neural oscillations in the basal ganglia are well-studied and have been described to correlate with behaviour. However, the mechanisms underlying this correlation and their functional significance are not well understood. Here, a computational model of the basal ganglia is developed and fitted to experimental recordings of nuclei of the basal ganglia after cortical stimulation and used to predict the causal mechanisms of different frequency bands. This new model allowed the researchers to observe that inputs related to motor tasks induced beta and gamma frequency oscillations as seen in vivo and identified which network pathways are required to observe these frequencies. The evidence in this study suggests that this new model can provide a coherent framework to analyse several features of the healthy basal ganglia and sets the basis for a better comprehension of basal ganglia-related pathologies like Parkinson's disease.
Frequency and function in the basal ganglia: the origins of beta and gamma band activity
Alexander Blenkinsop
Added on: 09-30-2021
Immune response to induce pluripotent cells evaluated ex vivo in donor cells
2017
Keio University School of Medicine, Tokyo, Japan
Stem cells are a promising source of novel therapies. In this context, induced pluripotent stem cells (iPSC) derived from somatic cells are now attracting much attention in regenerative medicine. To achieve clinical use of iPSC, a cell bank with diverse tissue compatibility markers is necessary to provide cells to a diversity of patients with minimum rejection. In the present study, the researchers evaluated the significance of tissue compatibility matching in hiPSC differentiated to Neural Stem /Progenitor Cell using different in vitro assays based on the co-culture of cells. The results showed low immune response even when cells are not matched which would indicate that a cell bank may not be so crucial to ease clinical use. It is important to verify whether these in vitro results are reproducible in a clinical setting.
Evaluation of the immunogenicity of human iPS cell-derived neural stem/progenitor cells in vitro
Masaya Nakamura, Hideyuki Okano
Added on: 09-20-2021
Regeneration of neural cells with cell therapy in vitro
2017
Academy of Military Medical Sciences, Beijing, China(1)
Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, China(2)
Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, China(2)
Alzheimer's disease is the most prevalent dementia and one of the most known neurodegenerative diseases. So far, there is no effective cure to stop or reverse it. Several types of therapeutic strategies based on the use of stem cells have been investigated. Here, human dental pulp stem cells are used to reverse the degeneration of okadaic-induced damage on human neuroblastoma cells. This model reproduces the retraction of dendrites and increase of cytotoxicity seen in neurodegeneration, which is counteracted by co-culture with human dental pulp stem cells. Several assays of this model confirmed that these stem cells not only stop neurotoxicity but are able to restore the normal morphology of neural cells. Additionally, it was possible to significantly reduce the phosphorylation of tau protein after treatment. These results show the potential of human dental pulp stem cells to induce regeneration of neural cells in the context of neurodegeneration and opens the road for further studies in this direction.
Dental pulp stem cells promote regeneration of damaged neuron cells on the cellular model of Alzheimer's disease
Xuetao Pei(1), Huixia He(2)
Added on: 08-17-2021
Beta-secretase 1 activity as a biomarker of dementia progression
2017
Capital Medical University, Beijing, China
Alzheimer's disease is the most prevalent form of dementia. However, diagnostic tools and pathology biomarkers are still scarce. The activity of beta-secretase 1 in cerebrospinal fluid has been investigated as a potential biomarker for mild cognitive impairment and Alzheimer's disease. But the methodology to extract cerebrospinal fluid is invasive. In this study, patients with mild cognitive impairment and patients with probable Alzheimer's disease were recruited to measure plasma beta-secretase 1 activity matched to cognitive follow-up during 3 years. The results show that beta-secretase 1 activity is significantly increased in demented patients compared to controls and in those evolving from mild cognitive impairment to probable Alzheimer's disease compared to cognitively stable patients. Thus, it seems that plasma beta-secretase 1 activity can be a biomarker for Alzheimer's disease but also can predict the transition from mild cognitive impairment to probable Alzheimer's disease.
Increased plasma Beta-Secretase 1 may predict conversion to Alzheimer’s disease dementia in individuals with mild cognitive impairment
Rena Li
Added on: 08-27-2021
Nanoparticle-based therapeutic strategy to reduce amyloid burden
2017
University of Milan Bicocca, Monza, Italy
Amyloid-beta accumulation in the brain is a major hallmark of Alzheimer's disease and still up to today the most accepted cause explanation for the onset and development of the disease. Recently, nanoparticles have been shown to be able to sequester amyloid-beta 42 after functionalization. In this study, liposomes were functionalized either with phosphatidic acid, or a modified apolipoprotein E (ApoE)-derived peptide, or with a curcumin derivative to try to reduce the levels of amyloid-beta 42 in cerebrospinal fluid or plasma samples from Alzheimer's disease or Down's syndrome patients. The nanoparticles treated with ApoeE derived peptide and phosphatidic acid showed significant binding to amyloid-beta 42 present in the cerebrospinal fluid. Similar results were obtained in plasma samples. The researchers give evidence that suggests that pre-treated liposomes can be a potential therapeutic approach to reduce the amyloid-beta burden in the brain by eliminating it from the body fluids circulation.
Multifunctional liposomes interact with Abeta in human biological fluids: therapeutic implications for Alzheimer's disease
Elisa Conti
Added on: 08-22-2021
Neurotoxic mechanisms in differentiated neuroblastoma cells
2017
Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
Parkinson's disease is a devastating neurodegenerative disorder characterized by a massive loss of dopaminergic neurons that leads to motor and cognitive decline and, ultimately, death. Despite big efforts in developing therapeutic strategies against this disease, there is no effective cure. A major concern in Parkinson's research is the lack of human in vitro models that can facilitate drug screening and the study of molecular mechanisms in an easy and cost-effective way. In this study, a human neuroblastoma cell line is characterized undifferentiated and after differentiation with retinoic acid and compared after treatment with the neurotoxic compound 6-hydroxydopamine. The results show that differentiated cells had characteristics related to neuronal phenotypes with dopaminergic features. When treated with 6-hydroxydopamine, differentiated cells were more sensitive to toxicity, although having higher basal resistance to oxidative stress. Moreover, the inhibition of dopamine transporter was protective only for differentiated cells. In summary, the researchers demonstrate that undifferentiated and differentiated human neuroblastoma cells have distinct phenotypes with different features and react differently to toxic compounds. Additionally, the data presented here support the use of retinoic acid differentiated cells as an in vitro platform to study pathological mechanisms and develop new therapeutical approaches for Parkinson's disease.
RA differentiation enhances dopaminergic features, changes redox parameters, and increases dopamine transporter dependency in 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells
Fabio Klamt, Fernanda M Lopes
Added on: 09-03-2021
New imaging agent to visualize early-stage amyloid-beta plaques
2017
La Trobe University, Victoria, Australia
Alzheimer's disease is one of the most prevalent neurodegenerative diseases. The most accepted theory assumes that the formation of amyloid-beta plaques is the causative process of the onset and development of the disease. However, until today, post-mortem brain analysis remains the only certain way to diagnose the disease. Therefore, there is a need to detect amyloid-beta plaques in the early stages of the disease to be able to properly design therapeutic strategies. Here, several analogues of Tc-99m have been designed to detect amyloid-beta plaques with medical imaging techniques. The results show that one of these complexes was able to bind to amyloid-beta plaques in samples of human frontal cortex from patients with Alzheimer's disease. This can open the door to a reliable, easy source of imaging agents that can pave the road to an early diagnosis and follow-up of Alzheimer's disease.
Rhenium(i) complexes of N-heterocyclic carbene ligands that bind to amyloid plaques of Alzheimer's disease
Peter J Barnard
Added on: 08-23-2021
Patients' immune cells used to understand the involvement of receptors in multiple sclerosis
2017
Lausanne University Hospital, Epalinges, Switzerland
Multiple sclerosis (MS) is a frequent chronic inflammatory disease of the central nervous system leading to neurologic disability and lifelong morbidity in young adults. Immune cell migration is a key point in the disease process. In the present study, the researchers aimed at discovering the potential role of chemotactic receptor EBI2 in MS. Immune cells were isolated from patients and analyzed by flow cytometry and tested for migration in vitro. The data show that EBI2 is functionally expressed on memory T cells. These data suggest a significant role for EBI2 in T cell migration, notably in patients with MS. Further studies on EBI2 involvement in autoimmunity may lead to an improved understanding of MS physiopathology.
EBI2 expression and function: robust in memory lymphocytes and increased by natalizumab in multiple sclerosis
Caroline Pot
Added on: 10-19-2021
A model system for stroke research
2017
Charité – Universitätsmedizin Berlin, Berlin, Germany
A model platform is established that simulates human brain tissue in two and three-dimensional systems. Human neurons and brain organoids are designed to study complex disease processes and develop new treatments for stroke. Various methods of stem cell biology, chemical biology, biophysics and structural biology were combined to investigate the complex disease processes of acute neurodegeneration in stroke and to improve drug development for treatment.
Schlaganfallforschung: Modellsystem kann Tierversuche ersetzen
Harald Stachelscheid
Added on: 05-25-2020
Biochemical diagnosis of Parkinson's disease
December 2016
The University of Texas School of Medicine at Houston, Houston, USA
Parkinson's disease is a devastating neurodegenerative disorder characterized by a massive dopaminergic loss that leads to motor and cognitive decline and, ultimately, death. Despite its high prevalence, there is a lack of diagnostic tools that allow a non-invasive biochemical evaluation to help in the early diagnosis and monitoring of the disease. One of the main pathological processes in Parkinson's disease is the accumulation of alpha-synuclein aggregates, which can be detected in small quantities in patients' cerebrospinal fluid. Here, a protein misfolding cyclic amplification is used to detect minimum amounts of alpha-synuclein aggregates, through a strategy of signal amplification. After the first validation with synthetic oligomers in vitro, this technique allowed for the identification of 88.5% of Parkinson's disease patients, with a specificity of 96.9% when using samples of patients with different neurodegenerative disorders. Additionally, the results of this test highly correlated with the severity of the disease. Here, the researchers propose a new non-invasive diagnostic approach to efficiently identify and discriminate Parkinson's patients, with a potential use in monitoring of the disease.
Development of a biochemical diagnosis of Parkinson disease by detection of α-synuclein misfolded aggregates in cerebrospinal fluid
Claudio Soto
Added on: 09-04-2021
Amyloid-beta anti-aggregation drug assessment
November 2016
Jagiellonian University Medical College, Cracow, Poland
Amyloid-beta aggregation is one of the hallmarks of Alzheimer's disease and, in the amyloid hypothesis, the main driver of its pathogenesis. In the last years, it has been the targeted pathological process to design therapeutical strategies. In this study, a computational approach is described to study inhibitory molecules of amyloid-beta aggregation. The researchers used molecular docking and all-atom molecular dynamics simulations and found out that the number of backbone hydrogen bonds is related to the anti-aggregation properties of these compounds and that these were able to destroy the beta-sheet amyloid structures. Here, valuable data is provided that can be potentially used for the design of novel inhibitors of amyloid-beta aggregation in Alzheimer's disease.
Computational approach for the assessment of inhibitory potency against beta-amyloid aggregation
Marek Bajda
Added on: 08-16-2021
Brain fMRI scans during TV watching
October 2016
Otto-von-Guericke University, Magdeburg, Germany
Functional magnet resonance imaging (fMRI) brain scans were performed on human volunteers while watching films or TV shows. With this non-invasive method, it was possible to make human-relevant estimations about the activity of different areas of the brain or the temporal memory during certain video sequences.
A studyforrest extension, simultaneous fMRI and eye gaze recordings during prolonged natural stimulation
Michael Hanke
Michael Hanke et al. Scientifc Data 2016 [518]
Informationsdienst Wissenschaft [519]
StudyForrest [520]
Added on: 05-25-2020
Limitations of a human in vitro blood-brain barrier model
October 2016
Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
The integrity of the blood-brain barrier is an essential feature of a healthy central nervous system. Consequently, several pathologies involve a defective blood-brain barrier. Decreased clearance of amyloid-beta at the blood-brain barrier has been observed in pathologies related to amyloidogenesis. In this study, a human brain endothelial cell line is evaluated as a model for amyloid-beta clearance along the blood-brain barrier. This model could only regulate the permeability of large molecules, allowing for substantially increased permeability of small molecules. Moreover, barrier formation for amyloid-beta was completely absent along the basolateral to apical transport. Furthermore, the development of tight junctions was incomplete. Overall, the investigated model showed important limitations in the study of clearance of amyloid-beta at the blood-brain barrier. The researchers bring new information about the limitations of this human model that should be further investigated before it is applied to study pathologies that involve amyloidogenesis.
Limitations of the hCMEC/D3 cell line as a model for Aβ clearance by the human blood-brain barrier
Marcel M Verbeek
Added on: 08-17-2021
Oxidative stress resistant cells for transplantation
October 2016
Mayo Clinic, Jacksonville, USA
Parkinson's disease is a devastating neurodegenerative disorder that results in a massive dopaminergic neuronal loss that leads to motor dysfunction, cognitive decline and, ultimately, death. Many factors have been described as a potential cause leading to the death of neurons, such as oxidative stress. The overproduction of reactive oxygen species can lead to DNA damage, and this has been proposed to be a major cause of dopaminergic neuronal death in Parkinson's patients. In recent years, cell replacement therapy has arisen as a potential therapeutic solution. However, cell survival is limited due to the neurotoxic environment present in the areas of transplantation. Here, a new approach is developed to increase cell survival upon transplantation by introducing a mutated H2AX gene to induce DNA repair and avoid apoptosis. The results show that dopaminergic neuron-like cells obtained from bone marrow-derived mesenchymal stromal cells with expression of the mutated H2AX have higher resistance to DNA damage and decreased levels of apoptosis after exposure to ultraviolet radiation or MPP+ treatment. In this study, the researchers develop a new strategy to obtain neuron-like cells that are more resistant to neurotoxic environments, which has great potential in developing cell replacement applications in neurodegenerative diseases.
Genetic modification of H2AX renders mesenchymal stromal cell–derived dopamine neurons more resistant to DNA damage and subsequent apoptosis
Dennis W Dickson, Peizhou Jiang
Added on: 09-01-2021
Protocol to culture human microglia
October 2016
Northwestern University, Chicago, USA
Microglia are the resident macrophages of the central nervous system. They are immune cells and have a wide range of physiological functions. Our current knowledge of this cell type relies mainly on rodent models, but differences in biological features with human samples have shown the need to obtain reliable techniques to use human microglia in in vitro studies. The main limitation for this is that currently there is no protocol that offers the opportunity to maintain human microglia in culture for a long time and for a high number of passages. To solve this, in this study a new protocol is developed based on the use of several growth factors that overcomes this limitation. The cells maintained their features and functions even in high passage numbers. Also, cultured human microglia was responsive to different activators. Additionally, microglia from Alzheimer's disease brains showed the same characteristics as from normal brains. The researchers propose a new method to be able to reliably culture microglia for long-term and high passages, which will give the opportunity to investigators to extend the mechanistic studies in human microglia from different patient profiles.
Postmortem adult human microglia proliferate in culture to high passage and maintain their response to amyloid-β
Changiz Geula
Added on: 08-23-2021
Alzheimer's disease research by screening inhibitory molecules targeting acetylcholinesterase
2016
Amrita University, Kochi, India
Cognitive decline in Alzheimer's disease might be led by dysregulation of acetylcholine, known as the cholinergic hypothesis. For this reason, several treatment strategies for this neurodegenerative disorder are based on targeting the inhibition of acetylcholinesterase, for example with donepezil, but which can cause severe side effects. In this study, a 3D-pharmacophore model using specific inhibitors was used for sequential virtual screening from small-molecule databases. Five molecules, selected based on their docking scores and pharmacokinetic properties, were then tested against the crystal structure of human acetylcholinesterase to reveal their binding mechanisms. After confirming their ADMET profiles, these molecules were subjected to Ellman's assay to assess their inhibitory activity, which for three of the five selected molecules was shown to be weaker than Donepezil. Here, the researchers propose a methodology that can lead to the discovery of existing molecules that can have better inhibitory activity of acetylcholinesterase than those used currently in clinical applications.
Integration of common feature pharmacophore modeling and in vitro study to identify potent AChE inhibitors
C Gopi Mohan, Krishnakumar N Menon
Added on: 08-15-2021
Computational model to study side effects of deep brain stimulation
2016
Indian Institute of Technology Madras, Chennai, India
The subthalamic nucleus has been described to have a central role in conflictive decision making. Furthermore, in Parkinson's disease patients with deep brain stimulation surgery in the subthalamic nucleus, it was observed that conflictive decision making was impaired leading to impulsive behaviour. Here, a 2D computational model of different components of the basal ganglia is used to decipher the mechanisms behind these adverse effects. This model was complemented with experimental data and used to compare the outcome of probabilistic learning tasks in different groups of untreated and treated Parkinson's patients and a group that underwent deep brain stimulation surgery in the subthalamic nucleus. The results showed that treated groups made impulsive (small reaction time) decisions which led to poor performance. Moreover, depending on the position of the electrode for the deep brain stimulation in the subthalamic nucleus, there was a decrease in neural activity. Finally, antidromic activation of the globus pallidus externa decreased reaction time in deep brain stimulation patients without altering learning abilities. Overall, this model allowed the researchers to elucidate the potential causes of conflictive decision making alterations in Parkinson patients with deep brain stimulation in the subthalamic nucleus that can be further studied in experimental setups.
Probing the Role of medication, DBS electrode position, and antidromic activation on impulsivity using a computational model of basal ganglia
V. Srinivasa Chakravarthy
Added on: 09-24-2021
Functional human midbrain-like organoids
2016
Genome Institute of Singapore, Singapore, Singapore
The authors developed 3D multilayer midbrain organoids with functionally mature and electrically active dopaminergic neurons from human iPSCs. Importantly, unlike 2D cell cultures, the human midbrain organoids produce neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues and are implicated in Parkinson’s disease.
Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin-producing neurons.
Huck-Hui Ng
Added on: 05-25-2020
Modulation of tyrosine hydroxylase expression for therapeutical strategies
2016
Iran University of Medical Sciences, Tehran, Iran
Tyrosine hydroxylase dynamics have been studied in Alzheimer's and Parkinson's disease and schizophrenia patients for some time now. The decrease in its levels influences catecholamine synthesis and this shows to be impaired in several neurological disorders. Here, the effects on tyrosine hydroxilase expression of noggin and different self-assembling nanofibers are investigated in neuron-like cells derived from human endometrial-derived stromal cells. The results show that BMHP-1 and laminin nanofibers induced higher cell viability through Wnt/beta-catenin signaling pathway, as assessed by Bcl2 and beta-tubulin III gene expression in neuroblastoma and neuron-like cells. While in other nanofibers other genes were induced, only in the laminin encapsulated cells in 2D cell culture with noggin-rich media was possible to observe overexpression of tyrosine hydroxylase. Overall, the researchers propose a new methodology to increase the expression of tyrosine hydroxylase through the encapsulation and treatment of induced neurons as a therapeutical strategy in different neurological disorders.
Noggin along with a self-assembling peptide nanofiber containing long motif of laminin induces tyrosine hydroxylase gene expression
Shima Tavakol
Added on: 08-31-2021
3D model of human iPSC-derived neural cells
2016
Florida State University, Tallahassee, USA
Human pluripotent stem cells are growing as a powerful tool to obtain unaccessible human cell material. In the last years, this method is increasingly used to model neurodegenerative diseases, as it allows to obtain human brain cells. Despite its popularity, the mechanisms of differentiation are still not well defined. In this study, human pluripotent stem cells are differentiated in a 3D context with specific modulation of the sonic hedgehog pathway. The results show that the modulation of this signalling pathway produced cells expressing glutamatergic or motor-neuron markers. Moreover, these cells had electrical activity and responded differently to different biomolecules targeting specific cell processes, showing that they are physiologically active. The researchers have developed a 3D platform of human neural cells that can be a powerful tool to increase translationality of disease modelling and drug discovery.
Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses
Yan Li
Added on: 08-20-2021
Organoids for modelling Zika virus exposure
2016
Johns Hopkins University School of Medicine, Baltimore, USA
The authors developed a miniaturized spinning bioreactor (SpinΩ) to generate forebrain-specific organoids from human iPSCs that recapitulate key features of human cortical development, notably including a distinct human-specific outer radial glia cell layer, which is absent in other animals. The authors also developed protocols for midbrain and hypothalamic organoids. Finally, the forebrain organoid platform could successfully be used to model Zika virus exposure, infection and resulting microcephaly. Therefore, this versatile platform is suitable for modelling human brain development and disease and for compound testing, including potential Zika antiviral drugs.
Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure.
Guo-li Ming, Hongjun Song
Added on: 05-25-2020
Neuroblastoma patients response to immunotherapy predicted by genetic profiling
2016
Memorial Sloan Kettering Cancer Center, New York, USA
Half of the patients with neuroblastoma (NB) have a high-risk disease at diagnosis with poor long-term survival. Monoclonal antibody (mAb) therapies directed at disialoganglioside GD2 mediate the action of Natural Killer cells (NK cells) and have been a major advancement in the treatment of NB. NK cells activity rely on the presence and interaction of certain cell surface receptors and ligands. In the present study, the researchers aimed at understanding if a specific combination of one cell surface receptor and ligand could help to predict the outcome of patients treated with monoclonal antibodies. A cohort of patients was genetically profiled for the presence of receptor and ligand and was correlated with patients outcomes following treatment. The results showed the best outcome when the patient has weak interacting receptors and ligands, hence potentially helping the prediction of prognosis.
KIR3DL1 allelic polymorphism and HLA-B epitopes modulate response to anti-GD2 monoclonal antibody in patients with neuroblastoma
Katharine C. Hsu
Added on: 09-17-2021
Development of a human model for tauopathies
Company 2016
Janssen Pharmaceutica N.V., Beerse, Belgium
Tau aggregation is a pathological process present in several neurodegenerative diseases and has become increasingly interesting as an alternative therapeutic target in Alzheimer's disease. Nevertheless, human models are scarce and there is a need to develop new methodologies that allow scalable assays to reproduce key features of tauopathies in a human context. In this study, transduced human iPSC were used to generate human cortical neurons in 3D conditions to develop a model that can reproduce tau aggregation. Moreover, AlphaLISA technology was used to detect aggregated tau in a high-throughput screening format. The results show that the developed set-up produces reproducible results with different cell lines and among different uses, proving that this can be a powerful tool to investigate potential therapeutic strategies for tauopathies.
Development of a scalable, high-throughput-compatible assay to detect tau aggregates using iPSC-derived cortical neurons maintained in a three-dimensional culture format
Alfredo Cabrera-Socorro
Added on: 08-19-2021
Transcriptomic profile of human induced dopaminergic neurons
2016
Montana State University, Bozeman, USA
Parkinson's disease is characterized by a massive loss of dopaminergic neurons. Recently, cell replacement therapy through the generation of induced dopaminergic neurons from human pluripotent stem cells has been proposed as a potential treatment. In this study, the transcriptional profiles of induced cells are compared against human primary dopaminergic neurons. After protocol optimization, it was possible to produce human induced dopaminergic neurons. In cells derived from Parkinson's patients, it was possible to distinguish a small subset of genes with altered expression. The transcriptomic analysis showed that the expression profiles of induced dopaminergic cells and primary midbrain neurons had differences, especially in genes related to neuronal maturation. Here, the researchers propose an improved protocol to generate dopaminergic neurons from human pluripotent cells that, when differentiated, can retain Parkinson's related features to be used in disease modelling. However, the protocols need to be further improved to generate fully functional induced dopaminergic neurons that closely resemble primary cells before using these cells in cell replacement therapy.
Transcriptional comparison of human induced and primary midbrain dopaminergic neurons
Renee A Reijo Pera
Added on: 08-31-2021
Bioreactor platform for neuronal culture
2016
National Research Council of Italy, Rende, Italy
One of the main problems of neuronal culture "in vitro" modelling has been the heterogeneous nutrient distribution. To overcome this problem, this study presents a membrane bioreactor that allows having a homogeneous and controlled microenvironment. Using a human neuroblastoma cell line, the researchers could produce a complex 3D functional active neuronal network, as is shown by the oxygen uptake and glucose consumption and the expression of synaptophysin. Furthermore, this model could be used to model amyloid beta-induced neurotoxicity: inducing cytotoxicity and oxidative stress in neuronal cells. This toxic effect was prevented using crocin. The researchers propose a solution to have a constant nutrient flow that makes it possible to obtain functional neuronal cultures with a homogeneous microenvironment what could potentially improve "in vitro" drug testing and development for neurodegenerative diseases.
Neuronal membrane bioreactor as a tool for testing crocin neuroprotective effect in Alzheimer’s disease
Loredana De Bartolo
Added on: 08-09-2021
Development of dopaminergic synapse computational model
December 2015
University of Ulster, Londonderry, United Kingdom
Homeostatic dopamine release is essential for the proper function of the brain, and the disruption of the dopaminergic system leads to neurological disorders. Currently, there is a lack of efficient and integrated models that allow linking in one model the molecular and neuronal circuit levels of the dopaminergic system. Here, the researchers try to develop a realistic computational model that efficiently represents a dopaminergic pre-synaptic terminal. Starting from an already established computational model, it was possible to simplify it and reduce it to two time-scale models. Moreover, both the original and the reduced model have similar dynamics, while the reduced version is more computationally efficient and can be used to investigate underlying key mechanisms. Finally, this reduced model was combined with a spiking neuronal model, with a later inclusion of an autoreceptor-mediated inhibitory current, to realistically simulate dopaminergic neuronal behaviour. In conclusion, a new integrated computational model is developed and represents the first steps towards an efficient computational platform to simulate the dopaminergic system, which could have great potential in drug discovery and development.
Integrated dopaminergic neuronal model with reduced intracellular processes and inhibitory autoreceptors
KongFatt Wong-Lin
Added on: 09-11-2021
Mutations involved in congenital heart disease identified in exosome of large patients cohort
December 2015
Columbia University Medical Center, New York, USA(1)
Harvard University, Boston, USA(2)
Icahn School of Medicine at Mount Sinai, New York, USA(3)
University of Pennsylvania, Philadelphia, USA(4)
Yale University, New Haven, USA(5)
Yale University School of Medicine, New Haven, USA(6)
Harvard University, Boston, USA(2)
Icahn School of Medicine at Mount Sinai, New York, USA(3)
University of Pennsylvania, Philadelphia, USA(4)
Yale University, New Haven, USA(5)
Yale University School of Medicine, New Haven, USA(6)
Newborns with congenital heart disease (CHD) have a greater risk of extra-cardiac congenital anomalies (CA) and neurodevelopmental disorders (NDD). In the present study, the researchers aimed at understanding better the genetic factors at play. The researchers performed exome sequencing on 1213 CHD parent-offspring trios and identified an excess of mutations in genes highly expressed in developing heart and brain and involved in morphogenesis, chromatin modification, and transcriptional regulation. The study details mutations common or specific to CHD, NDD, and CA. In conclusion, this study on a large patient cohort provides opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.
De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies
Wendy K. Chung(1), Christine E. Seidman(2), Bruce D. Gelb(3), Elizabeth Goldmuntz(4), Richard P. Lifton(5), Martina Brueckner(6)
Added on: 11-28-2021
Computational model of Parkinson's disease symtoms
November 2015
RWTH Aachen University, Aachen, Germany
Parkinson's disease is characterized by a progressive loss of dopaminergic neurons that leads to a reduction of dopamine in the basal ganglia. One of the consequences of this pathology is the freezing of articulatory movements during speech production. To further investigate this phenomenon, this study uses a computational approach to simulate syllable sequencing tasks by modelling the cortico-basal ganglia-thalamus-cortical action selection loop altering dopamine levels. Two parameters were used to represent the effects of D1 and D2 receptors and allow to differentiate and modify the different dopamine levels in the striatum. The results show that by decreasing dopamine by 50% it was possible to replicate the freezing effect after less than 5 syllable productions. Moreover, the model allowed to discriminate that dopamine level reduction in D1 receptors was more preeminent in freezing of action selection in speech. The model used here allowed to reproduce the symptomatology of Parkinson's disease and to elucidate potential mechanisms that can induce this behaviour.
Reduction of dopamine in basal ganglia and its effects on syllable sequencing in speech: a computer simulation study
Bernd J Kröger
Added on: 09-23-2021
Human stem cell model of neuromuscular junction affected by the autoimmune disorder myasthenia gravis
November 2015
Sloan-Kettering Institute for Cancer Research, New York, USA
Myasthenia gravis is an autoimmune disorder that selectively targets neuromuscular junctions. The potential application of pluripotent stem cell (PSC) - derived neurons in regenerative medicine and disease modelling ideally requires their integration into complex functional human networks or tissues. Yet, one of the most important properties of neurons, namely their ability to form functional synapses and transmit information to appropriate downstream targets, remains largely unexplored in human organoids and other PSC-based model systems. In the present study, the researchers aimed at establishing a neuromuscular model by in vitro co-culturing of human PSC derived into spinal motorneurons and human myoblast-derived skeletal muscle. The disease was modelled by incubating these co-cultures with autoantibodies from myasthenia gravis patients. The model was shown to be able to simulate muscle contraction under the control of the neurons. Further, the data showed a reversible reduction in the amplitude of muscle contractions when using the autoantibodies. In conclusion, this neuromuscular junction assay has a significant potential for modelling neuromuscular diseases and regeneration.
Functional connectivity under optogenetic control allows modeling of human neuromuscular disease
Lorenz Studer, Julius A. Steinbeck
Added on: 10-28-2021
Mitochondrial biomarker for Parkinson's disease
November 2015
Newcastle University, Newcastle upon Tyne, United Kingdom
During ageing, mitochondrial biogenesis is progressively reduced. This is also true for the brain, and mitochondrial dysfunction has been linked to neurodegenerative disorders, like Parkinson's disease, for several decades now. In this study, the mitochondrial DNA copy number are investigated in multiple tissues from patients with Parkinson's disease to validate mitochondrial DNA as a biomarker for the disease. The results showed that both in peripheral blood samples and substantia nigra pars compacta there is a reduction of mitochondrial DNA copy number in Parkinson's patients, but not in the frontal cortex. Here, the researchers confirmed that mitochondrial DNA copy number is reduced in the affected areas of the brain of Parkinson's patients, but not in other areas. However, the variation of mitochondrial DNA in the substantia nigra pars compacta was reflected in the peripheral blood samples, which indicates that it could be an easily accessible potential diagnostic biomarker for Parkinson's disease.
Reduced mitochondrial DNA copy number is a biomarker of Parkinson's disease
Gavin Hudson
Added on: 09-11-2021
Retinoic acid differentiated neuroblastoma cells for Parkinson's modelling
November 2015
Mahidol University, Bangkok, Thailand
Parkinson's disease is a neurodegenerative disorder characterized by a massive loss of dopaminergic neurons. Despite big efforts, there is no effective cure yet. One of the major problems is the lack of in vitro human models that can be used for mechanistic studies of the disease and drug testing. A human neuroblastoma cell line has been used as a dopaminergic neuronal model for Parkinson's disease. Here, this human neuroblastoma cell line is compared in undifferentiated and retinoic acid differentiated conditions through transcriptomic analysis of apoptosis after treatment with MPP+ and the expression of tyrosine hydroxylase. Immune-based techniques showed that the levels of tyrosine hydroxylase have different dynamics in undifferentiated and differentiated cells, where tyrosine hydroxylase increases progressively along with neuritic outgrowth. Moreover, the concentration of MPP+ to induce cytotoxicity in both groups was different, being two times higher in differentiated cells. Low-dose MPP+ treatment increased the expression of apoptosis-related markers in undifferentiated cells with no significance in the differentiated group. In this study, retinoic acid differentiated human neuroblastoma cells are proposed as an accessible and easy-to-use Parkinson's in vitro model to study pathological mechanisms and perform drug testing.
Differential expression of tyrosine hydroxylase protein and apoptosis-related genes in differentiated and undifferentiated SH-SY5Y neuroblastoma cells treated with MPP+
Permphan Dharmasaroja
Added on: 09-03-2021
MicroRNA profiles for the diagnosis of Parkinson's and Alzheimer's disease
October 2015
Zhejiang University, Hangzhou, China
Clinical diagnosis of Parkinson's and Alzheimer's disease is difficult at early stages with a high risk of mixed diagnosis. Therefore, there is a need to develop tools that can reliably differentiate these diseases, as it is extremely important to start the disease-specific treatment as early as possible. Here, a microRNA profiling method is developed to analyse the exosomal microRNAs isolated from the cerebrospinal fluid of patients with Parkinson's and Alzheimer's disease. The researchers found several microRNAs differentially expressed in Parkinson's exosomes in the cerebrospinal fluid from both healthy controls and Alzheimer's patients. Afterwards, a computational method was used to analyse the enriched pathways in the Parkinson's microRNA profiles. Moreover, they found that there were other types of RNA that were also differentially expressed in exosomes of cerebrospinal fluid in Parkinson's disease and Alzheimer's disease patients. Altogether, these data support the idea of using exosomal RNA from the cerebrospinal fluid as a reliable biomarker sensitive enough to make a differential diagnosis of Parkinson's disease.
Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease
YaXing Gui
Added on: 08-23-2021
Neural constructs for predicting neural toxicity
2015
Morgridge Institute for Research, Madison, USA
Human pluripotent stem cell-based in vitro models that mirror human physiology have the potential to cost-effectively assess the developmental neurotoxicity of chemicals. Here, human embryonic stem (ES)-derived neural progenitor cells, endothelial cells, mesenchymal stem cells and microglia/macrophage progenitors were combined on synthetic hydrogels and cultured in a serum-free medium to model cellular interactions in the developing brain. The progenitor cells self-assembled into 3D neuronal constructs with distinct populations of neurons and glia, interconnected vascular networks and branching microglia. The replicate constructs were reproducible by RNA sequencing (RNA-Seq) and expressed genes for neurogenesis, vascular development and microglia. Using machine learning, a predictive model was built from these RNA-Seq for the neuronal constructs exposed to a training set of 60 toxic and non-toxic chemicals and then predicted in a blind trial with a set of 10 additional compounds. The model correctly classified 9 of the 10 additional chemicals. This combined strategy demonstrates the value of cell-based assays for predictive toxicology and should be useful for assessing the safety of both drugs and chemicals.
Human pluripotent stem cell-derived neural constructs for predicting neural toxicity
James A. Thomson
Added on: 11-09-2021
New human microglial marker
2015
Meiji Pharmaceutical University, Tokyo, Japan
Microglia are the resident macrophages of the central nervous system. In recent years, they have been described to have an important role in several neurological disorders. However, it is still difficult to discriminate resident microglial cells from infiltrating macrophages and this interferes with the study of human microglia. In this study, the researchers try to find a new marker that is exclusively and consistently expressed in human microglia. After a first comparative analysis in microglial transcriptome datasets, TMEM119 is identified as a candidate marker, which is found to be consistently expressed in immortalised human microglia in different conditions. This marker is also described to be a better discriminator from infiltrating macrophages that express currently used microglial markers. Finally, there were no differences in the expression of TMEM119 in different subsets of microglia and between control and diseased human brains, clarifying that this can be a reliable marker to be used to study microglia in different conditions. These results offer new possibilities to better isolate and study human microglia and show the possibility of using human models to improve the translational value of glial biology studies.
TMEM119 marks a subset of microglia in the human brain
Jun-ichi Satoh
Added on: 08-16-2021
Development of amyloid beta detection technique
2015
Université Paris-Sud, Châtenay-Malabry, France
The development of reliable diagnostic tools for Alzheimer's disease is a critical effort to tackle and treat the disease. Several advancements have been made but the available techniques still have inconveniences that limit its clinical potential. Here, a sample pre-treatment for a higher detection sensitivity of different amyloid-beta peptides in cerebrospinal fluid of Alzheimer's patients is proposed. The system is based on a pre-concentration of the samples with magneto-immunocapture, that could achieve x100 concentrations, continued with on-bead fluorescent labelling. The results show that it was possible to concentrate the peptides and this process allowed for more sensitive detection and separation of the peptides, giving the possibility to be better analyzed. Also, different commercial antibodies were tested and a microfluid-based system was developed to allow for rapid sample testing. In this study, the researchers develop a new tool that could improve the detection of amyloid peptides for early diagnosis of Alzheimer's disease and they successfully tested a proof of concept pilot system that could evolve into an easy-handling device to perform high-throughput analysis of patient's samples.
Magneto-immunocapture with on-bead fluorescent labeling of amyloid-β peptides: towards a microfluidized-bed-based operation
Claire Smadja
Added on: 08-26-2021
New biomarker for synaptic function in Alzheimer's disease
2015
University of Gothenburg, Mölndal, Sweden
Alzheimer's disease affects several physiological processes of the central nervous system. Synaptic dysfunction and degeneration are one of the hallmarks of the pathology and it is thought to begin early in the disease. Neurogranin is a postsynaptic protein localized in several areas of the brain. It was shown that neurogranin is increased in cerebrospinal fluid in Alzheimer's disease. Here, cerebrospinal fluid and plasma samples from Alzheimer's disease patients were analyzed to investigate neurogranin as a biomarker of Alzheimer's disease. The results showed that there are unique neurogranin peptides only present in human plasma and not in cerebrospinal fluid, and vice versa. Neurogranin was significantly increased in cerebrospinal fluid of Alzheimer's patients, while plasma levels were similar and there was no correlation between neurogranin levels in both fluids. In this study, new plasma neurogranin peptides are described, which could be further investigated to be potential biomarker targets. Additionally, it is confirmed in human samples that neurogranin is increased in Alzheimer's disease and it could be further developed as a biomarker for synaptic function in neurodegenerative disorders.
Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls
Hlin Kvartsberg
Added on: 08-22-2021
Biomarker identification for Alzheimer's disease
2015
Korea Basic Science Institute, Chungbuk, South Korea(1)
Université de Lille 1, Villeneuve-d’Ascq, France(2)
Université de Lille 1, Villeneuve-d’Ascq, France(2)
Alzheimer's disease is the most prevalent form of dementia and is characterized by progressive brain degeneration that leads to cognitive deficits and death. Despite the increasing knowledge available, the onset mechanisms and biomarkers of the pathology remain unclear. Here, hippocampal CA4 and dentate gyrus subfields from Alzheimer's patients were investigated with mass spectrometry-based proteomic analysis combined with label-free quantification to identify potential biomarkers. The results elucidated 113 potential markers with a 2-fold difference in protein levels in Alzheimer's patients compared to controls. Five of these proteins were identified and validated as putative Alzheimer's biomarkers. Moreover, five upstream signalling factors were identified from the 113 differentially regulated proteins. Altogether, the researchers provide new information about altered proteins in Alzheimer's disease that could potentially be used as biomarkers for the diagnosis of the disease and, also, open the door to new therapeutical targets.
Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer’s disease
Young Mok Park(1), Isabelle Fournier(2)
Added on: 10-01-2021
In silico model of cerebrospinal venous circulation
2015
IRCCS Santa Maria Nascente, Milano, Italy
In recent years, the relationship between extracranial venous system abnormalities and central nervous system (CNS) pathologies has been scrutinized but no clear link has ever been demonstrated. In the present study, the researchers aimed at shedding light on the matter by creating an in silico model of cerebrospinal venous drainage from anatomical data taken from the literature. Effects of the obstruction of the main venous outflows were simulated and the model was used to reanalyze the 112 Multiple Sclerosis patients. The model developed in the study can predict physiological and pathological behaviours with good fidelity. Further development of the model should take into account different body positions.
An anatomy-based lumped parameter model of cerebrospinal venous circulation: can an extracranial anatomical change impact intracranial hemodynamics?
Maria Marcella Laganà
Added on: 11-28-2021
Kinase cascade shown to be involved in inflammation process using multiple sclerosis patients' cells
2015
Fondazione Santa Lucia, Rome, Italy
Multiple sclerosis is an immune-mediated disorder, in which autoantigen-specific T cells infiltrate the central nervous system and carry out an immune reaction against self-structures, leading to progressive demyelination and consequent nervous damage. The p38 kinase plays an essential role in human lymphocyte development, proliferation and cytokine release. In the present study, the researchers aimed at uncovering a possible link between the p38 signalling pathway and the breakdown of the immunological balance in MS. Using immune cells isolated from MS patients and healthy donors, the researchers showed that the p38 signalling pathway is implicated in the generation of a certain subset of lymphocytes and the release of certain cytokines. Interestingly, the data show that cells from MS patients display altered responsiveness of the p38 cascade, resulting in increased p38 phosphorylation upon stimulation. These findings suggest that the p38 signalling pathway, by modulating the Th17 differentiation and response, is involved in the pathogenesis of MS, and open new perspectives for the use of p38 inhibitors in the treatment of Th17-mediated autoimmune diseases.
The p38 mitogen-activated protein kinase cascade modulates T helper type 17 differentiation and functionality in multiple sclerosis
Luca Battistini
Added on: 10-30-2021
Network model to study dopamine and serotonin in the basal ganglia
2015
Indian Institute of Technology Madras, Chennai, India
The basal ganglia have been proposed to contribute to risk-based decision making. However, the computational principles and neural correlates of risk computation are not well-known in this area. In previous studies, a model of reinforcement learning of the basal ganglia was proposed based on the interaction between dopamine, responsible for reward prediction error, and serotonin, related to risk prediction error. Here, the previous model is developed into a detailed network model of the basal ganglia that incorporates anatomical and cellular-level data to evaluate the contributions of dopamine-serotonin interactions in risk and reward-punishment sensitivity. An important feature of this expanded model is that it includes dopamine D1 and D2 co-expressing medium-sized spiny neurons and how dopamine and serotonin mediate their activity. The results show that serotonin has significant modulatory effects on D2 and D1-D2 co-expressing neurons, predicting the diverse functions of serotonin in the basal ganglia in risk sensitivity and reward-punishment learning. Moreover, this model could also predict the impairment of these functions in Parkinson's disease. The researchers show in this study that serotonin might have an important role in reward-punishment learning and could be a potential target to complement dopamine-based therapies in patients with deficits.
A network model of basal ganglia for understanding the roles of dopamine and serotonin in reward-punishment-risk based decision making
V. Srinivasa Chakravarthy
Added on: 09-22-2021
Protocol to isolate and analyze cells from human brains
2015
Ruhr-Universität Bochum, Bochum, Germany
As the world population becomes older, the study of the brain in normal ageing and neurological disorders grows in interest. However, despite the advances in the field, there are several limitations in the study of specific cell types at the molecular level. Current isolation protocols do not allow the study of isolated intact neurons. Recent updates in laser microdissection techniques are attractive to overcome the present limitations in the isolation of brain cells. In this study, a detailed protocol is defined to isolate and analyze neurons from human postmortem brain. The results showed that this workflow allowed to successfully freeze, section and stain human tissue for laser microdissection, which was validated by mass spectrometry. The sample preparation employed in this study also would allow for other analytical techniques. Overall, here a protocol is presented that allows isolation of human brain cells, which could be a powerful tool to study specific brain cell's functions and molecular mechanisms.
Enrichment of single neurons and defined brain regions from human brain tissue samples for subsequent proteome analysis
Caroline May, Katrin Marcus
Added on: 09-04-2021
ELISA assay to detect a new potential biomarker of Alzheimer's disease
2015
Radboud University Medical Centre, Nijmegen, Netherlands
The brain is the organ that has the highest oxygen consumption in the body, making it more prone to undergo oxidative stress after any dysregulation. Therefore, oxidative stress is observed in many neurodegenerative diseases, and it is thought that the oxidation of individual proteins can be disease-specific. In Alzheimer's disease, it has been observed that peptidyl-prolyl isomerase is sensitive to oxidation. Here, human post-mortem hippocampus samples of Alzheimer's patients are analysed with a newly developed ELISA assay to detect and quantify oxidised peptidyl-prolyl isomerase. The researchers found that their new method successfully measured the oxidised protein present in lysates of the patients' hippocampus and that it was possible to observe a rise in the oxidised ratio in early Alzheimer's. Overall, this study presents evidence of a new tool that could easily detect a new potential biomarker of Alzheimer's disease. In the near future, this technique should be tested with other fluids to further develop its possibilities.
A multifunctional ELISA to measure oxidised proteins: oxPin1 in Alzheimer's brain as an example
Marcel M Verbeek
Added on: 08-23-2021
Generation of human neural progenitor cells for cell therapy
2015
Suranaree University of Technology, Nakhon Ratchasima, Thailand
Human pluripotent stem cells popularity has grown over the last years as they offer an unlimited source of human cells for cell therapy strategies. This is because they have several characteristics that allow them to be maintained in culture without losing key features, like pluripotency. Recently, several studies have investigated the use of cell therapy strategies in neurodegenerative diseases that present massive neuronal loss, like Alzheimer's, Parkinson's or Huntington's disease. In this study, human embryonic stem cells were differentiated into dopaminergic neurons in a two-step protocol that includes the generation of neural progenitors. Using small molecules the researchers could generate neural progenitors with similar characteristics to embryonic neural progenitor cells. Afterwards, these progenitors were treated with growth factors that induced their differentiation into dopaminergic neurons that expressed midbrain neuronal markers. Here, a new protocol is developed that allows the generation of human neural progenitor cells that can serve as an unlimited source of cell material for cell therapy strategies based on dopaminergic neuron replacement in Parkinson's disease.
Neural progenitor cells derived from human embryonic stem cells as an origin of dopaminergic neurons
Parinya Noisa
Added on: 08-30-2021
Multi-approach study of tripeptides to depolymerize amyloid beta fibrils
2015
Polish Academy of Sciences, Warsaw, Poland(1)
Slovak Academy of Sciences, Košice, Slovakia(2)
Slovak Academy of Sciences, Košice, Slovakia(2)
The aggregation of amyloid-beta and the formation of fibrils has been proposed as the main cause driving Alzheimer's disease pathology. Despite the lack of effective treatments, there is experimental data that suggests that the reversion of amyloid aggregation can reduce the symptoms of the disease. In this study, all the tripeptides were screened for their amyloid beta depolymerization capabilities. Different computational approaches revealed four tripeptides with high binding affinity to amyloid aggregates and showed that the interaction is preferably done at the hydrophobic regions of the fibrils. Also, the researchers performed "in vitro" assays to experimentally validate the candidates. They found that the four tripeptides had significant depolymerizing activity and their DC50 values were in the micromolar range, confirming the results obtained in the "in silico" analysis. This method describes a set of tripeptides with high binding affinity to amyloid beta fibrils and the mechanisms of these interactions that lead to amyloid beta depolymerization and that could be a potential therapeutic approach for Alzheimer's disease that can be further tested in future studies.
In silico and in vitro study of binding affinity of tripeptides to amyloid β fibrils: implications for Alzheimer’s disease
Mai Suan Li(1), Zuzana Gazova(2)
Added on: 08-15-2021
Parkinson's microfluidic based model
2015
University of Luxembourg, Esch-sur-Alzette, Luxembourg
Parkinson's disease is a neurodegenerative disorder characterized by the loss of nigrostriatal dopaminergic neurons. Despite being one of the most studied neural pathologies, there is no cure to prevent or restore the loss of these cells. One of the critical limitations to have successful treatments is the lack of models that faithfully reproduce the human disease. In recent years, the advancements in the use of human iPSC from patients have allowed to develop human models that can reproduce specific traits of human diseases that are difficult to study. Here, human iPSC coming from Parkinson's patients are differentiated in a microfluidic system that allows the 3D culture and in situ characterization of the cells. The results show that after 30 days of differentiation, the efficiency was similar to other usually used protocols and produced tyrosine hydroxylase positive cells that were electrophysiologically active. The researchers develop in this study a new model that integrates the generation of human iPSC-derived dopaminergic neurons in a microfluidic system that could be used to systematically characterize patient-derived cells and help to develop personalized therapies for Parkinson's disease.
Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture
Ronan M T Fleming
Added on: 08-30-2021
Telomere's length may influence leukocyte inflammatory profile in Alzheimer's disease
2015
University of Milan, Milan, Italy
Alzheimer's disease is a multifactorial neurodegenerative disease that involves several cell types. Leukocytes are one of these cell types, and their telomere length has been related to the development of the disease. Here, Alzheimer's patients were recruited to investigate the influence of leukocyte telomere length on Alzheimer's progression. The mini mental state examination correlated with telomere length and slow-progression Alzheimer's patients showed shorter telomeres compared to healthy and fast-progression ones. Moreover, Interleukin 10 has been related to inflammatory alleviation, thus the researchers compared its production among peripheral blood mononuclear cells' stimulation with amyloid-beta. Slow-progression patients' cells were the only ones of the three groups to show significant differences. The results elucidate a new possible mechanism that can be interesting to understand leukocyte's telomeres contribution to the disease and the therapeutic possibilities that may arise from it.
Leukocyte telomere length in Alzheimer’s disease patients with a different rate of progression
Beatrice Arosio
Added on: 08-20-2021
Peripheral red blood cells interact with amyloid-beta
2015
Tianjin Medical University, Tianjin, China
Alzheimer's disease progression affects several cell types in the body. It has been reported in vitro that amyloid-beta can bind and disrupt red blood cells. Peripheral red blood cells of Alzheimer's disease patients were analyzed to find out their potential interactions with amyloid-beta. It was found that the presence of elongated red blood cells was significantly higher in Alzheimer's patients and that the major part of the red blood cells in these samples was amyloid binding-positive. Furthermore, these interactions seemed to induce different morphologies. The results of this study support the further exploration of the potential of red blood cells morphology as an easily accessible feature to use as a biomarker for Alzheimer's disease.
The peripheral blood of Aβ binding RBC as a biomarker for diagnosis of Alzheimer's disease
Jie Lan
Added on: 08-23-2021
Role of a neuropeptide in inflammation studied on primary and immortalized human cells
2015
University of Nottingham, Nottingham, United Kingdom
Substance P (SP) is a neuropeptide that shows properties comparable to cytokines and exerts different effects in autoimmune inflammation. SP and its neurokinin-1 receptor (NK1R) are expressed by various immune cells and their role has been demonstrated in autoimmune conditions like multiple sclerosis (MS). In the present study, the researchers aimed at better understanding the role of SP and NK1R in human immune cells and their relationship with a number of cytokines. The researchers performed a number of in vitro analyses on primary immune cells isolated from donors and of human immortalized immune cell lines. The cells were treated with SP or cytokines and levels of expression of each component were assessed. Mutual interactions exist with SP enhancing the cytokines, and SP and NK1R expression being differentially but potentially synergistically regulated by these cytokines. The data suggest a proinflammatory role for SP in autoimmune inflammation, probably stimulating the recruitment of immune cells. In conclusion, SP may be a therapeutic target in MS.
Reciprocal regulation of substance P and IL-12/IL-23 and the associated cytokines, IFNγ/IL-17: a perspective on the relevance of this interaction to multiple sclerosis
Cris S. Constantinescu
Added on: 10-30-2021
Transcriptomic analysis of human striatum development
2015
University of Barcelona, Barcelona, Spain
A better understanding of neurodevelopment is necessary to properly comprehend brain physiology in different conditions. Stem cell technologies advances in recent years allow the generation of human models through the recapitulation of human development in vitro. However, there are still certain limitations and a proper evaluation of the protocols should be done by comparing the in vitro process to their in vivo counterparts. Here, human samples of the whole ganglionic eminence and adult striatum are processed and analyzed by quantitative high-throughput gene expression analysis to elucidate the gene expression patterns that drive striatum development. The results showed that the relative expression of specific genes between brain areas is a key factor in their proper development. Afterwards, these expression profiles were used to characterize the differentiation of human pluripotent stem cells through whole ganglionic eminence identity towards adult striatum-like cells. Overall, the researchers establish a transcriptomic profile to evaluate stem cell-derived tools for in vitro modelling or cell therapy strategies.
Quantitative high-throughput gene expression profiling of human striatal development to screen stem cell–derived medium spiny neurons
Josep M Canals
Added on: 11-28-2021
Biomarker characterization in Alzheimer's disease
December 2014
Emory University, Atlanta, USA
The early diagnosis of Alzheimer's disease is a critical step to decide treatment strategies. However, very few reliable techniques have been developed to properly detect the onset and progression of the disease. One of these is the biomarker detection in cerebrospinal fluid. Several markers have been described to be altered in the cerebrospinal fluid of Alzheimer's patients, but this is still subjected to serious limitations: confounding factors affecting the detection of these biomarkers and interoperator variability among them. In this study, the researchers aim to characterize the biological and technical factors affecting the detection of Alzheimer's biomarkers in cerebrospinal fluid from patients at different stages of the disease. The results show that extensively used protocols detect lower levels of amyloid-beta 42 than the real amount present in the samples. It was also found that the partial levels detected by these protocols correlate to the total amount of amyloid-beta and other factors. Moreover, it was confirmed that the levels of detected amyloid-beta 42 are directly affected by other factors like apoJ or apoE levels. Overall, here it is shown that the levels of suspended amyloid-beta 42 detected in cerebrospinal fluid may be influenced by other factors and could be used to study some processes triggered in the disease, but for better clinical determination of the disease stage total amyloid-beta 42 and suspended forms should be taken into account together.
CSF beta-amyloid 1-42 - what are we measuring in Alzheimer's disease?
William T Hu
Added on: 08-26-2021
Characterization of the SH-SY5Y human neuroblastoma cell line
December 2014
University of Luxembourg, Esch-sur-Alzette, Luxembourg
Immortalized human cell lines are a powerful tool to model human diseases in a cost-effective manner. The human neuroblastoma cell line SH-SY5Y is a popular cell line used to study pathological features of neurodegenerative diseases, especially Parkinson's disease. However, the relevance of this model in neurodegenerative diseases has not yet been studied. Here, the SH-SY5Y cell line has been characterized using a systemic genomics approach: combining genomic, transcriptomic and proteomic data to evaluate its suitability as a model for neurodegenerative diseases. The results show that there is consistency across the different -omics analyses. Moreover, all the major pathways involved in Parkinson's disease are intact, thus it is a good candidate line to model the disease. However, the genetic integrity is not ideal for some other neurodegenerative diseases, therefore it should be taken into account as a potential limitation when using this cell line in other disorders. In this study, the SH-SY5Y cell line is characterized and validated for the first time using a system genomics approach, increasing the consistency of the model and giving useful data to the scientific community about the benefits and limitations of using this model to study neurodegenerative diseases.
Systems genomics evaluation of the SH-SY5Y neuroblastoma cell line as a model for Parkinson’s disease
Patrick May, Abhimanyu Krishna
Added on: 09-04-2021
Computational tools to explore oxidative and immunological stress in dementia
December 2014
San Raffaele Scientific Institute, Milan, Italy
Mild cognitive impairment can increase the risk of developing Alzheimer's disease. Therefore, prediction tools are needed to know the prognosis of the disease. Pro-oxidative state and neuroinflammation are increasingly linked to dementia. So, a new computational model based on artificial neural networks is used in this study to decipher the relationship between oxidative stress and inflammation in Alzheimer's disease and mild cognitive impairment. The results show that machine learning was able to build an algorithm that, using a small amount of immunological and oxidative stress parameters, accurately classified Alzheimer's disease and mild cognitive impairment. Also, it was possible to establish a correlation between global immune deficit and cognitive impairment with a new non-linear mathematical model. Overall, this study proposes a new method to discriminate between different types of dementia, to accurately predict the possible prognosis of these cases and also to decipher new mechanisms of the pathophysiology of these disorders, making it a potentially valuable tool for clinical applications.
A global immune deficit in Alzheimer’s disease and mild cognitive impairment disclosed by a novel data mining process
Maira Gironi
Added on: 08-05-2021
Correlation of amyloid beta and alpha-synuclein levels in human samples
December 2014
University of Bristol, Bristol, United Kingdom
Lewy bodies, widely present in Parkinson's disease, are often seen in Alzheimer-type pathologies. While Alzheimer's disease is characterized by an accumulation of amyloid-beta, Parkinson's is by an accumulation of alpha-synuclein. Some studies have also shown that the accumulation of these two aggregates can be correlated. Here, the correlation between amyloid-beta peptides and phosphorylation of alpha-synuclein is studied in postmortem human brain samples, from different cases of Parkinson's disease and dementia with Lewy bodies, and in a human neuroblastoma cell line overexpressing human alpha-synuclein. The results showed that insoluble and soluble phosphorylated alpha-synuclein correlated positively and negatively, respectively, with insoluble amyloid-beta. Moreover, amyloid-beta and insoluble phosphorylated alpha-synuclein levels were higher in demented than in non-demented patients. Insoluble alpha-synuclein also correlated positively with the Braak stage but negatively with the mini-mental state examination. Furthermore, neuroblastoma cells exposed to aggregated amyloid-beta 42 had increased levels of phosphorylated alpha-synuclein. In summary, this study shows that phosphorylated alpha-synuclein concentration in brain tissue correlates with amyloid-beta levels and with the dementia state, which could be potentially used to monitor the Lewy body disease-induced dementia.
Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson’s disease
Seth Love
Added on: 09-10-2021
Proteomic profiling of amyloid-beta plaque-related serum proteins
December 2014
Plaxgen Inc., Sunnyvale, USA
Amyloid-beta accumulation in aggregates is thought to be the leading cause of Alzheimer's disease. Despite the many advances in the field, it is still challenging to diagnose Alzheimer's in the early stages of the disease. Therefore, there is a need to find reliable biomarkers that can be easily detected from the very onset of the disease. Here, a new method based on proteomic profiling is used to identify serum proteins related to amyloid-beta plaque formation to be used as biomarkers. The results show that there are effectively amyloid beta-related serum proteins. Among them, a considerable percentage are unique for amyloid plaque particles in Alzheimer's serum compared to cholesterol, alpha-synuclein and tau plaque particles. Additionally, some of them were also able to form amyloid-beta plaques in vitro. Overall, the researchers show a new, potentially non-invasive, method to easily detect proteins and identify proteins related to amyloid-beta plaque formation to be used as biomarkers.
Plaque array method and proteomics-based identification of biomarkers from Alzheimer's disease serum
Shanmugavel Madasamy
Added on: 08-23-2021
Computational model to study misfolded protein dynamics in the brain
November 2014
Montreal Neurological Institute, Montreal, Canada
The aggregation of misfolded proteins is associated with several neuropathologies. Amyloid-beta is one of them, and its mechanisms of propagation and deposition are not well understood. In this study, a computational approach is used to generate an epidemic spreading model for misfolded protein dynamics that reconstructs individual lifetime intra-brain propagation and the factors that promote it. Using PET amyloid-beta datasets, the model was able to reproduce amyloid-beta deposition patterns in human brains and proposes several mechanisms that explain the amyloid beta-driven onset and progression in Alzheimer's disease, but also its deposition's dynamics in the normal ageing brain. It was also capable of relating the accumulation of amyloid-beta to several other factors and the interactions between them. In summary, this model allows to relate misfolded protein dynamics in the brain with individual risk factors and clinical and demographic data, opening the door to explore the mechanisms of misfolded proteins associated with ageing and neurological pathologies.
Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders
Alan C. Evans, Yasser Iturria-Medina
Added on: 08-08-2021
Development of amyloid-beta detection tool for Alzheimer's disease
October 2014
Université Paris-Sud, Chatenay-Malabry, France
Detection and determination of different amyloid-beta peptides are critical for the proper development of diagnostic tools for Alzheimer's disease. Despite the big advances in the last years, it is still difficult to detect the onset and pathological evolution of the disease without relying on cognitive tests. Here, two polymers are tested to be used in glass microchips to reliably separate several amyloid-beta peptides detected by fluorescence. The results show that the polymers had different adsorptions of amyloid-beta. The polymer having the lowest adsorption was further validated in the glass microchips as linear and the limit of detection was found to be around 200nM. The system coated with this polymer allowed for the proper resolving of the different amyloid-beta peptides and it could be applied to the detection of these peptides in human cerebrospinal fluid samples. Thus, in this study, the researchers propose a new system that can evolve into a promising clinical application to detect different amyloid-beta peptides and their concentrations to establish them as biomarkers of onset and progression of the disease.
Neutral polymers as coatings for high resolution electrophoretic separation of Aβ peptides on glass microchips
Myriam Taverna
Added on: 08-26-2021
Biochip to diagnose Alzheimer's disease
2014
Medical University of Vienna, Vienna, Austria
Alzheimer's disease is a multifactorial disorder that leads to brain degeneration, provoking cognitive deficits and, ultimately, death. The causes of the disease are not yet clear and the only diagnostic tools available are neuropsychological tests and brain imaging. Recently, new diagnostic tests based on markers in cerebrospinal fluid have been proposed, but they require invasive approaches. Here, platelet lysates of different groups of patients with neurodegenerative diseases were analyzed using a fluorescence two-dimensional differential gel electrophoresis in independent discovery and verification sets to identify biomarkers of Alzheimer's disease related to platelets. The results show that it was possible to efficiently discriminate Alzheimer's patients through a sum score of four identified proteins. Afterwards, the researchers developed a high-throughput multiplex protein biochip to apply the described profile for the diagnosis of Alzheimer's disease. The method developed in this study allows to rapidly screen samples of potential patients of Alzheimer's disease in a non-invasive approach through the detection of newly proposed biomarkers in a high-throughput system.
A platelet protein biochip rapidly detects an Alzheimer’s disease-specific phenotype
Maria Zellner
Added on: 09-30-2021
Development of primary mixed human brain cultures
2014
Indiana University School of Medicine, Indianapolis, USA
Primary cultures are a basic tool in neuroscience. However, most of the time these cultures are done with rodent brains, associated with several limitations in the translational potential of the model. In this study, human fetal brains are used to produce mixed primary brain cultures. The results show characteristic features in human cultures not present in animal-based models. With the proper methods, it is possible to maintain brain cells for a long time in culture, producing different types of neurons and glia. Additionally, consistent production of amyloid-beta, tau and other characteristic markers of Alzheimer's disease is also described. Basically, the study presents a new human model with a detailed characterization that can be a powerful tool to enhance the translationality of neuroscience studies and help to better understand the mechanisms of human brain disorders, leading to new therapeutic approaches.
Human primary mixed brain cultures: preparation, differentiation, characterization and application to neuroscience research
Debomoy K Lahiri
Added on: 08-22-2021
Modified mesenchymal stem cells for Parkinson's cell therapy
2014
The 148th Hospital, Zibo, China
Parkinson's disease is a devastating neurodegenerative disorder that is characterized by a massive loss of dopaminergic neurons. Despite having a lot of attention, there is still no effective cure for it. Cell therapy has been growing in the last years as a feasible option for Parkinson's treatment and mesenchymal stem cells derived from human umbilical cord are gaining popularity. Here, human umbilical cord mesenchymal stem cells overexpressing HGF, a neuroprotective factor, have been used to treat neuroblastoma cells in a Parkinson's model based on MPP+ treatment. The results show that the supernatant from HGF overexpressing cells promoted the regeneration of neuroblastoma cells at higher efficacy than those that did not overexpress HGF. Additionally, the researchers decipher some mechanistic hints of this effect that point to the modulation of calcium signalling. In this study, a new potential approach is developed for the regeneration of damaged neurons in Parkinson's disease.
Human umbilical cord mesenchymal stem cells Infected with adenovirus expressing HGF promote regeneration of damaged neuron cells in a Parkinson’s disease model
Yun-Liang Wang, Bing Han
Added on: 08-31-2021
Mathematical model for disturbed tau dynamics
2014
University of California Davis, Davis, USA
Tau proteins are critically important in the stabilisation of axonal microtubules and their dysregulation is present in several neurodegenerative diseases such as Alzheimer's disease, tauopathies, and chronic traumatic encephalopathy. However, how the disturbed tau protein dynamics leads to the collapse of axonal microtubules is still not well understood. Here, the researchers provide a simplified mathematical model to study the mechanics of microtubule-tau bundles in neuronal axons where taus are removed. The results show the different conditions of tau binding conditions and the potential role of dynamic instability in microtubule's collapse. The main conclusion of which is that well before dynamic instability is relevant, the mechanical damage done to microtubule bundles at low tau binding rates is already irreversible. Therefore, this could be a very useful model to properly design treatment strategies for tau related pathologies.
Simulated cytoskeletal collapse via Tau degradation
Daniel L Cox
Added on: 08-09-2021
Amyloid beta-induced microvasculature dysfunction
2014
Phoenix Veterans Affairs Health Care System, Phoenix, USA
Alzheimer's disease is the most prevalent neurodegenerative disorder and is characterized by progressive brain degeneration that leads to cognitive decline and death. Amyloid beta has been extensively proposed to be the driving cause of the disease and, currently, there is growing evidence that it may also lead to vascular dysfunction and hypoperfusion during the progression of the disease. Thus, there is a need to investigate the mechanisms of amyloid beta-induced endothelial dysfunction and oxidative stress in human microvasculature. Here, abdominal subcutaneous arterioles from living humans and post-mortem leptomeningeal arterioles are used to study how amyloid beta affects vascular dilatation and the production of reactive oxygen species. The results showed that exposure to amyloid beta impaired dilatation of adipose and leptomeningeal arterioles, which could be reversed with the use of an antioxidant. Moreover, amyloid beta also induced increased oxidative stress in adipose arterioles. The researchers propose a model based on easily accessible tissue that can be obtained from living patients to study the mechanisms of amyloid beta-driven microvasculature dysfunction and opens the door to study new therapeutical approaches to counteract the pathological effects of amyloid beta in Alzheimer's disease.
Adipose and leptomeningeal arteriole endothelial dysfunction induced by β-amyloid peptide: A practical human model to study Alzheimer's disease vasculopathy
Raymond Q Migrino
Added on: 10-01-2021
Small molecule prevents amyloid-beta-induced neurotoxicity
2014
China Medical University, Taichung, Taiwan
Accumulation of amyloid-beta in the brain is one of the hallmarks of Alzheimer's disease and, in the amyloid hypothesis, the driving factor of the disease. To try to decrease the cytotoxicity of amyloid-beta in human neuronal cells, a peroxisome proliferator-activator receptor alpha agonist (Wy14643) is used in this study. When using Wy14643 on amyloid beta-treated neuronal cells, the researchers were able to increase cell viability after only 24 hours. In this context, the protein levels of several markers of apoptosis remained unchanged except for Endo G and AIF. Immunofluorescence assays showed that Wy14643 reduced the translocation of these two factors into the nucleus, which reduced DNA damage and apoptosis induced by amyloid-beta treatment. These results show that the activation of peroxisome proliferator-activator receptor alpha prevents amyloid beta-induced DNA damage and apoptosis of human neuronal cells and the mechanisms behind it. This study proposes a new therapeutical target in a human model that can be further translated into clinical applications to treat neurotoxicity in Alzheimer's disease.
PPARα activation attenuates amyloid-β-dependent neurodegeneration by modulating Endo G and AIF translocation
Nai Wen Chang
Added on: 08-16-2021
Model to predict and stratify Alzheimer's disease patients
2014
CHU de Montpellier and Université Montpellier I, Montpellier, France
Alzheimer's disease is the most prevalent form of dementia. Cerebrospinal fluid biomarkers have been widely used to diagnose and follow the evolution of the disease. However, the way these data are interpreted and how are used to predict the onset or the prognosis of the disease is not clearly established. Therefore, in this study, a biologic scale of probabilities is developed to properly predict and stratify potential patients of Alzheimer's disease. The researchers use cerebrospinal fluid samples from several memory clinics and they use different models combining levels of amyloid-beta 42, tau and phosphorylated tau. A simple model based on numbered classification of the biomarkers is developed and shown to be very efficient to predict and stratify the patients from the memory clinics. This was validated computationally and with an independent dataset from different centres. Overall, here a mathematical predictive model is presented that can help diagnose patients of Alzheimer's disease in the very early stages of the disease, or even before the onset, and correctly stratify them for treatment or clinical research purposes.
A diagnostic scale for Alzheimer’s disease based on cerebrospinal fluid biomarker profiles
Sylvain Lehmann
Added on: 08-29-2021
New compound against myasthenia gravis tested in patients' cells
2014
Maastricht University, Maastricht, Netherlands(1)
Weatherall Institute of Molecular Medicine, Oxford, United Kingdom(2)
Weatherall Institute of Molecular Medicine, Oxford, United Kingdom(2)
Myasthenia gravis (MG) is one of the best understood of the numerous autoimmune neurologic diseases. Treatment of MG relies primarily on glucocorticoids, often combined with broad-spectrum immunosuppressants but their efficacy and side effects vary greatly between patients, urging the need for more therapeutic strategies. In the present study, the researchers aimed at studying the potential use of another compound called Bortezomib which had been already used to eliminate malignant plasma cells in other diseases. The study was performed using thymus cells isolated from MG patients treated with bortezomib. The treatment killed long-lived plasma cells and halted their spontaneous production of autoantibodies. In conclusion, bortezomib appears promising for treating MG and possibly other Ab-mediated autoimmune or allergic disorders, especially when given in short courses at modest doses before the standard immunosuppressive drugs have taken effect.
Proteasome inhibition with bortezomib depletes plasma cells and specific autoantibody production in primary thymic cell cultures from early-onset myasthenia gravis patients
Pilar Martinez-Martinez(1), Mario Losen(1), Nick Willcox(2)
Added on: 10-30-2021
Mathematical model for alpha-synuclein molecular dynamics
2014
National and Kapodistrian University of Athens, Athens, Greece
Alpha-synuclein is involved in several pathologies and has been described to have a central role in Parkinson's disease. The profiles of expression of alpha-synuclein have been suggested to be correlated with familial and sporadic forms of the disease and result in the aggregation of fibrils in the form of Lewy bodies in neurons. However, there is a lack of understanding of the molecular mechanisms of alpha-synuclein that can lead to the prevention or to a potential cure of Parkinson's disease. Here, a mathematical biomolecular reactions model is developed to describe the molecular dynamics of intracellular alpha-synuclein. Furthermore, experimental data of alpha-synuclein overexpression is obtained using a human neuroblastoma cell line to validate the simulated data generated with this model. The results show that in three hypothetical intervention scenarios the model is capable of simulating the cell viability outcome that fits with experimental data. This new model allows predicting alpha-synuclein dynamics in newly generated scenarios to estimate the underlying mechanisms that lead to proteolysis deregulation. This opens new possibilities in the study of alpha-synuclein and provides researchers with a powerful tool to test hypotheses prior to experimental tests.
In silico modeling of the effects of alpha-synuclein oligomerization on dopaminergic neuronal homeostasis
Elias S Manolakos
Added on: 09-23-2021
Fibroblasts facilitate permeability of an in vitro blood-brain barrier
2014
Yonsei University College of Medicine, Seoul, South Korea
To study the importance of fibroblasts in brain metastasis, several assays in several models are used. Also, two new 3D models are developed with human cells to study the permeability of a multicellular in vitro blood-brain barrier, transmigration and breast cancer cell colony formation. These new devices provide mechanistic insights into cancer-associated fibroblasts in breast cancer brain metastasis.
Cancer-associated fibroblast promote transmigration through endothelial brain cells in three-dimensional in vitro models
Nam Hoon Cho
Added on: 07-16-2021
Transthyretin as an oxymeter in neurodegenerative diseases
2014
Statens Serum Institut, Copenhagen, Denmark
Transthyretin is an abundant protein in the cerebrospinal fluid and has been found to be prone to oxidation due to changes in the oxidative profile. Several neurodegenerative diseases, like Alzheimer's disease, have oxidative stress as one of their main pathological processes. Thus, characterizing the oxidation profile of transthyretin in the cerebrospinal fluid of patients could be promising. Here, transthyretin isoforms have been profiled in Alzheimer's or mild cognitive impairment patients and controls with an immunoaffinity-mass spectrometry approach. The profile of transthyretin oxidation was correlated to common Alzheimer's biomarkers and diagnostic information. The results show that one specific transthyretin modification was found to be elevated in the cerebrospinal fluid of dementia patients, but no correlations were found with common biomarkers. Also, it was difficult to manipulate transthyretin ex vivo and further investigation is needed to improve the handling of cerebrospinal fluid samples. In conclusion, researchers could find some clues that point to the transthyretin oxidation profile as a potential biomarker to monitor the onset and evolution of neurodegenerative diseases that involve oxidative stress, but further studies need to be done to confirm these results.
Distinct transthyretin oxidation isoform profile in spinal fluid from patients with Alzheimer’s disease and mild cognitive impairment
Niels H H Heegaard
Added on: 08-29-2021
Dopaminergic differentiation ex vivo from human skin samples
2014
Newcastle University, Newcastle upon Tyne, United Kingdom
Parkinson's disease is a neurological disorder characterized by a massive loss of dopaminergic neurons. Despite being one of the most investigated neural pathologies, no effective cure has been discovered. In recent years, with the advancement of stem cell research, cell replacement therapies are surging as a real possibility to be applied for Parkinson's disease. Here, human epidermal neural crest stem cells are obtained from human samples of hairy skin to be differentiated into neural stem cells, that will be further maturated into dopaminergic neurons. The results show that after the first step of differentiation towards neural stem cell-like cells and a maturation step with defined factors, all the cells in culture had dopaminergic neuron-like gene expression patterns similar to those found in vivo in the human substantia nigra. The researchers propose in this study a new accessible cell source for ex vivo production of dopaminergic neurons in an easy-to-apply protocol. This could be further developed to establish fully functional neurons that could be used in Parkinson's disease cell therapy strategies.
Differentiation of human epidermal neural crest stem cells (hEPI-NCSC) into virtually homogenous populations of dopaminergic neurons
Maya Sieber-Blum
Added on: 08-31-2021
Computational model of dopaminergic neurons
November 2013
University of Tuebingen, Tübingen, Germany
Parkinson's disease is a devastating neurodegenerative disorder that is characterized by a progressive death of dopaminergic neurons that leads to motor and cognitive deficits and, ultimately, death. Despite having identified several pathological features of the disease, the mechanisms that cause the onset remains unknown. Here, the researchers propose a computational model of dopaminergic neurons based on several sub-models that include cellular processes involved in the homeostatic and pathological mechanisms present in Parkinson's disease. The model was investigated to find steady model states through the modulation of several experiments. The results show that this model can predict neuronal outcomes that fit previous observations and can be used to study how the manipulation of different cellular processes affect the pathological outcome in the cell. This study provides an in silico platform to simulate the behaviour of dopaminergic neurons and predict the outcome of potential dysregulations that are present in pathologies such as Parkinson's disease.
Parkinson’s disease: dopaminergic nerve cell model is consistent with experimental finding of increased extracellular transport of α-synuclein
Finja Büchel
Added on: 09-30-2021
Demonstration of genetic manipulations for in vitro modeling
November 2013
University of Konstanz, Konstanz, Germany
The lack of differentiated human cell types and the difficulties associated with their use and manipulation have previously hindered the development of human-based in vitro models. Here, a human conditionally-immortalized mesencephalic cell line is used to apply genetic modifications in the proliferative state to study their effects in the post-mitotic neurons. Several genetic modifications are done in this study, and the results show that it is possible to induce overexpression or knockdown of Parkinson's related proteins to modulate the physiological outcome of the cells. Also, the researchers introduce reporter genes to track the dynamics of different proteins or organelles in different cell compartments, which allows studying the modifications induced by toxic compounds used in Parkinson's models. Overall, a strategy is presented that offers the possibility to genetically manipulate a human neural progenitor cell line that can be differentiated into dopaminergic neurons to study changes in protein and organelle physiology in different pathological conditions in post-mitotic human cells.
Generation of genetically-modified human differentiated cells for toxicological tests and the study of neurodegenerative diseases
Stefan Schildknecht
Added on: 09-02-2021
Single-domain antibody to target human amyloid-beta 42
November 2013
Beijing Normal University, Beijing, China
Alzheimer's disease is the most prevalent form of dementia. No effective treatments to stop the onset or the progression of the disease are currently available. The most accepted theory establishes amyloid-beta aggregates as the cause of the onset and the development of the disease. Many efforts have been made in recent years to target amyloid-beta but no effective treatments have passed the clinical trials. Here, a human naïve phage library based on blood samples from six healthy people has been used to produce a single-domain antibody that recognizes specifically the oligomers of amyloid-beta 42. The Western blot and ELISA results show that this antibody binds specifically to human amyloid-beta 42 tetramer and nonamer oligomers but not to monomers or other oligomers. In this study, the researchers produce a new human phage display library that allows them to find a single domain antibody, which facilitates organ penetration, to target specifically amyloid-beta oligomers, which has the potential to be further developed as immunotherapy against Alzheimer's disease.
Construction of human Fab library and screening of a single-domain antibody of amyloid-beta 42 oligomers
Fei Dou
Added on: 08-29-2021
Dopaminergic neurons from multipotent stem cells
October 2013
Second Military Medical University, Shanghai, China
Human bone marrow multipotent stem cells have been used in the last decades as a source of cell material for cell therapy strategies. Mainly, the applications have been directed towards regeneration strategies of bone tissue, cartilages, or hepatic tissue. However, little is known about the potential of these multipotent stem cells to be used in neural regeneration. Here, aged human bone marrow multipotent stem cells were used to generate dopaminergic neurons that could be potentially used in Parkinson's disease therapies. The results show that these cells could be maintained in vitro for a long time, keeping the expression of pluripotent genes and could generate cells from the three germ layers. When induced with specific factors, it was possible to generate cultures with up to 70% of dopaminergic neurons that could secrete dopamine upon depolarization. In this study, the researchers propose a new source of cell material to develop autologous cell replacement strategies for Parkinson's disease, even from aged patients.
Directed differentiation of aged human bone marrow multipotent stem cells effectively generates dopamine neurons
Houqi Liu
Added on: 08-31-2021
Immunodetection of a potential biomarker of Alzheimer's disease
October 2013
DZNE - German Center for Neurodegenerative Diseases, Munich, Germany
Alzheimer's disease is the most prevalent form of dementia. However, it still remains difficult to diagnose. Several biomarkers have been proposed to detect the onset of the disease and follow the pathological evolution of patients, but it is still difficult to have clear separation in the levels of these biomarkers between affected patients and controls. Recently, new biomarkers have been proposed, like the alpha-secretase cleaved soluble amyloid precursor protein ectodomain. Some studies found reduced levels of this peptide in the cerebrospinal fluid of Alzheimer's patients, but it has been controversial as other researchers found opposite behaviours. These differences could arise from the lack of antibodies to specifically detect this cleaved product. Here, a new ELISA-like method is developed using a specific antibody to detect this peptide. The results show that the antibody has high specificity and can detect the cleaved peptide in human neural cells culture supernatant, in human cerebrospinal fluid and in serum. It was possible to detect a significant increase in cerebrospinal fluid of Alzheimer's patients and obtain better separation of affected individuals and controls compared to other methods. Overall, this method has the potential to be used in several applications both in basic research and clinical contexts to specifically measure a potential new biomarker for Alzheimer's disease.
A new sandwich immunoassay for detection of the α-secretase cleaved, soluble amyloid-β protein precursor in cerebrospinal fluid and serum
Stefan F Lichtenthaler
Added on: 08-30-2021
Vasoconstriction dynamics are altered in Alzheimer's disease
2013
Frenchay Hospital, Bristol, United Kingdom
Alzheimer's disease is a neurodegenerative disorder that leads, among other things, to cognitive decline and, ultimately, death. It is the most prevalent dementia, but there are no effective tools to predict it or diagnose it at very early stages before the symptomatology is already detectable. Reduced cerebral blood flow has been proposed to occur before the formation of amyloid-beta plaques and cognitive abnormalities. Endothelin-1 is a vasoconstrictor present in the brain that is produced by neurons, through endothelin-converting enzyme 2, and in endothelial cells, by endothelin-converting enzyme 1. The first two have been shown to be elevated in post-mortem Alzheimer's patients' brains and their activity is modulated by amyloid-beta 42 in vitro. In this study, postmortem brains from Alzheimer's patients were studied to identify abnormalities of endothelin-1 and the enzymes related to it. The results show that leptomeningeal blood vessels from post-mortem brains had reduced levels of endothelin-converting enzyme 1, but its activity and endothelin-1 release were increased in Alzheimer's disease vessels. When primary cultures of human brain endothelial cells were stimulated with amyloid-beta 40 or 42, the researchers could see an increase in endothelin-1 release, contrary to when they added also the antioxidant superoxide dismutase. Overall, here it is shown that amyloid-beta could modulate the activity of factors related to vasoconstriction partially through the production of free radicals. This opens new possibilities to study the different pathways involved in this phenomenon to try to find new biomarkers and therapeutic targets.
Endothelin-converting enzyme-1 activity, endothelin-1 production, and free radical-dependent vasoconstriction in Alzheimer's disease
Jennifer C Palmer
Added on: 08-30-2021
Computational tools to study human Superoxide Dismutase 2
2013
Federal University of Rio de Janeiro State, Rio de Janeiro, Brazil
Polymorphisms of the superoxide dismutase 2 gene have been related to the development of neurological disorders. In this study, all the known human variants of this gene were analysed with different algorithms. With this analysis and with well-fitted structural theoretical models, it was possible to see that all mutations lead to the pathogenicity of the protein. In the end, all this data, together with a phylogenic analysis, were included in a freely accessible database that can be used by biologists and clinicians. This will allow to further explore the outcomes of the mutations of the superoxide dismutase 2 gene in pathological processes in humans.
Structural modeling and in silico analysis of human Superoxide Dismutase 2
Joelma Freire De Mesquita
Added on: 08-06-2021
New tool to disrupt amyloid beta-fibril formation
2013
Indian Institute of Technology Guwahati, Guwahati, India
Alzheimer's disease is a neurodegenerative disorder with one of the highest prevalences. The cause of the disease is thought to be the pathological accumulation of amyloid-beta aggregates in the brain. There are several phenomena that can influence this pathological accumulation, with the enhanced levels of toxic metals being among them. Their accumulation can not only generate reactive oxygen species, accelerating the accumulation of amyloid-beta in Alzheimer's patients, but it can also interact and bind to amyloid-beta peptides. Therefore, controlling the interaction dynamics of toxic metals and amyloid-beta could help to decrease the levels of oxidative stress. Here, the researchers propose a non-toxic conjugated polymer that binds iron-containing proteins to interact with the iron present in amyloid-beta protofibril aggregates and decrease their accumulation. Cerebrospinal fluid from healthy individuals was doped with amyloid-beta 40 with and without iron to test the anti-aggregation activity of the polymer. The results show that the polymer was able to disrupt the fibril formation of amyloid-beta under physiological conditions in the cerebrospinal fluid samples, leading to less toxic forms of amyloid-beta peptides. This study brings a new tool in the treatment of Alzheimer's disease through the disruption of the pathological aggregation of amyloid beta and fibril formation.
A rapid and sensitive detection of ferritin at a nanomolar level and disruption of amyloid β fibrils using fluorescent conjugated polymer
Parameswar Krishnan Iyer
Added on: 08-29-2021
Plasma from dementia patients affects endothelial cells negatively
2013
Università Politecnica delle Marche, Ancona, Italy
In the last years, there is growing evidence that Alzheimer's disease might include vascular dysfunction. Endothelial cells have been suggested to be disrupted early in the development of Alzheimer's disease and this has been related to disturbed vascular homeostasis. Here, the plasma from patients with mild cognitive impairment or Alzheimer's disease was used to treat cultured human aortic endothelial cells. The results showed an impaired regulation of several parameters related to endothelial function in both groups of patients, but more pronounced in plasma coming from Alzheimer's patients. This study confirms that the plasma of demented patients can affect endothelial function negatively, emphasizing the urgency of investigating therapeutic approaches aimed at protecting the endothelium in early stages of dementia.
Effects of plasma from patients affected by mild cognitive impairment and Alzheimer's disease on cultured endothelial cells
Eleonora Salvolini
Added on: 08-22-2021
Computational approach to model estrogen regulation of amyloid beta production
2013
University of Illinois at Urbana-Champaign, Urbana, USA
Amyloid-beta accumulation in Alzheimer's disease is a complex process that is not well understood. Despite this, estrogen is known to influence the regulation of its production. Here, a computational approach is used to model the complex contribution of estrogen to amyloid-beta regulation. The results show that by using estrogen it is possible to induce the reduction of amyloid-beta levels. The model also shows the mechanisms behind this potential reduction and that the use of non-steroidal anti-inflammatory drugs could be used as an additional treatment. It also describes a series of other compounds that could be also used synergistically with estrogen to further decrease the amyloid-beta levels. The results show that this model could be used as a starting point for drug development and to understand the mechanisms behind them.
Exploring the contribution of estrogen to amyloid-beta regulation: a novel multifactorial computational modeling approach
Thomas J Anastasio
Added on: 08-08-2021
Mathematical modeling of reciprocal modulated reactions of the tau protein
Company 2013
EnVivo Pharmaceuticals, Watertown, USA
Hyperphosphorylation of tau protein is implicated in several neurodegenerative diseases. One of the approaches to tackle this process is to increase the levels of tau O-GlcNAcylation, as they are reciprocally regulated. Therefore, some therapeutical strategies are based on the inhibition of O-GlcNAcase. In this study, mathematical models are developed to analyse the dynamics of phosphorylation and O-GlcNAcylation of tau protein during O-GlcNAcase inhibition. The predictions show an increase of O-GlcNAcylated tau proportional to the inhibition levels and a non-dependent variable decrease of phosphorylated forms. This reduction in phosphorylated tau happens in short-term inhibitory scenarios and it is expected to return to its initial values under sustained inhibition, while O-GlcNAcylated proteins achieve higher steady levels. Furthermore, inhibition arrest is predicted to cause a temporal increase in phosphorylated tau levels. This model deciphers complex mechanisms in phosphorylation and O-GlcNAcylation co-regulation in different inhibitory strategies and can be a useful tool to design pharmacological interventions in scenarios where tau phosphorylation is a major pathological process.
A dynamic view to the modulation of phosphorylation and O-GlcNAcylation by inhibition of O-GlcNAcase
Cuyue Tang
Added on: 08-16-2021
Design of optimised beta secretase inhibitors
2013
University of Leeds, Leeds, United Kingdom
Amyloid-beta accumulation is one of the major Alzheimer's disease pathological processes. The first step in the production of this peptide is the cleavage of amyloid precursor protein by beta-secretase. Therefore, this secretase is an attractive target for inhibition strategies to tackle the progression of the disease, avoiding the accumulation of amyloid-beta. Here, a computational approach is used to design several nonpeptide beta-secretase inhibitors based on a biphenylacetamide scaffold. A new library of optimised ligands was generated and the newly designed molecules had more than a 10-fold higher binding affinity than their scaffold, as suggested by their IC50. Afterwards, a final selection was done based on a cytotoxicity "in vitro" assay with an immortalised human cell line, which revealed that one of the newly designed compounds had minimal cellular toxicity. This study presents a methodology that can be used for the design and initial screening of optimised compounds to modulate the activity of therapeutic targets.
Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
A Peter Johnson, Nigel M Hooper, Colin W G Fishwick
Added on: 08-16-2021
P-selectin dynamics in Alzheimer's disease
2013
The Vrinnevi Hospital, Norrköping, Sweden
Alzheimer's disease is a multifactor disorder that can induce alterations in different tissues. Recently, more attention is being driven to other areas apart from the central nervous system, such as the cardiovascular system. A lot of knowledge is being generated on this topic, but little is still known about the role of platelets in Alzheimer's disease. In this study, the aim was to investigate P-selectin, which co-localizes with amyloid precursor proteins and is found in endothelial cells, in Alzheimer's disease. P-selectin and surface-bound P-selectin were analyzed in circulating blood samples of moderate Alzheimer's patients. The results show that soluble P-selecting was found to be increased in Alzheimer's samples and surface-bound P-selectin was decreased upon in vitro agonist stimulation. In conclusion, the researchers show that Alzheimer's disease seems to influence the levels of circulating P-selectin and also platelet reactivity, opening the door to further research on this topic to explore and understand the consequences of Alzheimer's disease.
P-selectin paradox and dementia of the Alzheimer type: circulating P-selectin is increased but platelet-bound P-selectin after agonist provocation is compromised
Petter Järemo
Petter Järemo et al. Scandinavian Journal of Clinical and Laboratory Investigation 2013 [653]
EURL ECVAM [654]
Added on: 08-30-2021
Mechanistic insight into why women are more likely to get Alzheimer’s
December 2012
Massachusetts Institute of Technology, Cambridge, USA(1)
The Scripps Research Institute, La Jolla, USA(2)
The Scripps Research Institute, La Jolla, USA(2)
Protein S-nitros(yl)ation (SNO) is a post-translational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer’s disease (AD). To identify SNO proteins in AD brains, the researchers used mass spectrometry and analysed 40 postmortem AD and non-AD human brains from patients of both sexes. Increased S-nitrosylated complement component 3 (C3 ) levels were present in female over male AD brains. Mechanistically, they showed that the formation of SNO-C3 leads to increased synaptic phagocytosis, synapse loss and consequent cognitive decline. The study demonstrates robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.
Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3
Steven R. Tannenbaum(1), Stuart A. Lipton(2)
Added on: 01-05-2023
Simulation of the fibril formation typical for Alzheimer's disease
December 2012
University of California Irvine, Irvine, USA
Amyloid-beta aggregation and fibril formation are some of the hallmarks of Alzheimer's disease, but the mechanism that connects these phenomena with the onset of the disease is not yet clear. Before, it has been proposed that the formation of these fibrils follows a dock/lock mechanism. Therefore, in this study, the researchers use a simulation of two-dimensional ultraviolet spectroscopy to confirm this hypothesis. The signals generated can be used to monitor local dynamics and conformational changes in the secondary structure of amyloid-beta peptides, showing that these are in agreement with a dock/lock pathway. The results confirm that this method can be used to further explore the dynamics of protein aggregation.
Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy
Alfonso R Lam
Added on: 08-06-2021
Alzheimer's disease prediction model
November 2012
Radboud University Nijmegen, Nijmegen, Netherlands
Alzheimer's disease is one of the most prevalent neurodegenerative disorders. However, the available diagnostic tools are not efficient and there are severe limitations to predict the occurrence and the onset of the disease. Here, a prediction model is presented to estimate the probability of developing Alzheimer's disease based on amyloid-beta 42 and phosphorylated tau levels in cerebrospinal fluid together with patients' sex. The logistic regression analysis gives an estimation to calculate the probability of developing Alzheimer's disease and when this is applied to the validation data set, has a powerful discriminative ability. The researchers present, and validate, a prediction model that has the potential to be applied in memory clinics to assess the probability of patients developing Alzheimer's disease based on commonly used biomarkers.
A prediction model to calculate probability of Alzheimer’s disease using cerebrospinal fluid biomarkers
Petra E Spies
Added on: 08-28-2021
Cell-based botox batch test
Regulatory accepted CompanyNovember 2012
Allergan Inc., Irvine, USA
Botulinum neurotoxin serotype A (BoNT/A), usually referred to as Botox, is an effective therapeutic agent used to treat various diseases. It inhibits the signal transmission of nerve cells, which leads to muscle paralysis. This effect is used in the treatment of strabismus, torticollis, hyperhidrosis or bladder dysfunction, but also for aesthetic purposes such as relaxation of the facial muscles, which leads to wrinkle smoothing. Up to now, the toxin concentration of each batch was and is determined in animal tests. The so-called LD50 test determines the concentration at which 50 % of the mice in a group die. Here, an animal-experiment-free method is presented. BoNT inhibits vesicular neurotransmitter exocytosis by cleaving the protein SNAP25. The individual key steps of this reaction can be measured with CBPAs (cell-based efficacy assays). It uses differentiated human neuroblastoma cells (SiMa) and a sandwich ELISA that measures the BoNT/A-dependent intracellular increase in cleaved SNAP25. Allergan has validated this test for its products in the US, Canada and the EU, replacing the LD50 test for batch testing.
Botulinum neurotoxin serotype a specific cell-based potency assay to replace the mouse bioassay
Ester Fernández-Salas
Added on: 08-31-2021
Mathematical model of amyloid beta dynamics in the presence of gamma-secretase inhibitors
CompanyNovember 2012
AstraZeneca, Macclesfield, United Kingdom
The mechanisms of amyloid-beta accumulation in Alzheimer's disease are still not well-known. One unanswered question is the rise of amyloid-beta levels after treatment with gamma secretase inhibitors in some cell lines. In this study, a mathematical model is proposed to quantitatively describe the dynamics of amyloid-beta in cell lines that undergo this phenomenon compared to those that do not. The results show that the changes in the dynamics of the amyloidogenic and non-amyloidogenic pathways are driven by the accumulation of C-terminal fragment 99 of the amyloid precursor protein. Also, the model is able to reproduce the amyloid-beta profiles of humans treated with gamma secretase inhibitors. Overall, this study proposes an effective mathematical model that can be used to develop new therapeutics that target amyloid-beta production in Alzheimer's disease.
Interplay between α-, β-, and γ-secretases determines biphasic amyloid-β protein level in the presence of a γ-secretase inhibitor
Claus Bendtsen
Added on: 08-08-2021
Expansion of neural progenitors to produce dopaminergic neurons
2012
Karolinska Institute, Stockholm, Sweden
Parkinson's disease is characterized by a progressive loss of dopaminergic neurons. Currently, there are no efficient therapies that can disrupt or restore the massive neuronal loss, so new strategies are needed. Recently, a cell therapy approach consisting of grafting fetal midbrain tissue was tested as a proof-of-concept in patients. However, the cell material is very limited. Here, a new method of expansion of neural progenitor cells present in the human ventral midbrain fetal tissue is developed to produce large quantities of midbrain dopaminergic neurons. The results show that the production of neurospheres with these progenitor cells can largely expand the number of neural progenitors with a capacity to differentiate into midbrain dopaminergic neurons. The use of Wnt5a induced the differentiation of the expanded neural progenitors towards dopaminergic neurons that showed in vivo features. The final number of dopaminergic-like cells in these preparations was 6 times higher than in the original tissue. This study brings a new methodology that can help to produce large amounts of dopaminergic cells, reducing the amount of fetal tissue needed, to enhance the development of cell replacement therapy in Parkinson's disease.
Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens
Ernest Arenas
Added on: 08-30-2021
Mechanisms involved in amyloid beta production and secretion
2012
University of Konstanz, Konstanz, Germany
Differences in the processing of amyloid precursor protein in young and aged neurons are still not well described and might be important to understand and prevent the onset of Alzheimer's disease. In this study, a human embryonic neuronal precursor cell line is used to study the changes in amyloid precursor protein dynamics along with neuronal maturation and ageing. Differentiated neurons efficiently produced and secreted amyloid-beta, which could be inhibited by cholesterol depletion or secretase inhibition. In aged cells, there was an increase of amyloid-beta secretion without affecting the expression of upstream factors of the amyloidogenic pathway. This phenomenon was associated with GDNF present in the media via the upregulation of RET coreceptor, as other activation mechanisms of the last one were able to produce the same outcome. Inhibitors of protein kinase B completely blocked this effect and the increase of amyloid-beta levels. The results show a mechanism involved in the increased production and secretion of amyloid-beta in aged neurons that could be potentially used to study new therapeutic strategies targeting its up- or downstream regulators.
Control of Aβ release from human neurons by differentiation status and RET signaling
Diana Scholz
Added on: 08-17-2021
3D brain models for toxicity tests
CompanyNeuron-D GmbH, Dresden, Germany
Neuron D's 3D toxicity model of the human brain is suitable for testing various chemicals for their toxicity profiles in human neurons and neural stem cells. With customizable approaches, this model is highly flexible and allows investigating almost endless readouts such as stem cell activity, neurogenesis, neuronal network formation, biochemical events in the cells, changes in gene expression, epigenetic changes, migratory behaviour, synaptic activity, neurotransmitter release, morphological changes and many more. This model is suitable for the early selection of hit compounds in drug development studies.
3D-Tox
www.neurond.de
Added on: 11-21-2022
3D Glioblastoma ex vivo
CompanyNeuron-D GmbH, Dresden, Germany
Glioblastoma multiforme (GBM) is the most common malignant brain tumor among adult patients and is almost universally fatal. Despite the recent leaps in knowledge about the genome, epigenome, and transcriptome of GBM, clinical outcomes in GBM have not changed over the years. To investigate this disease the company Neuron D has developed a 3D cell culture drug testing platform for glioblastoma multiforme (GBM).
The 3D platform is based on the 3D starPEG-Heparin hydrogel technology. It enables drug developers to test the efficacy, safety and pharmacokinetics of candidate compounds for GBM in a three-dimensional, physiologically relevant tumor environment.
3D Glioblastoma ex vivo
www.neurond.de
Added on: 11-21-2022
3D human brain development model
CompanyNeuron-D GmbH, Dresden, Germany
The 3D brain development model of the company Neuron D recapitulates the developmental molecular programs of the human brain. All cortical neuronal subtypes are formed and reach a mature electrophysiological stage. This model is suitable for applications that require reliable human brain development systems. These include but are not limited to the research of neurodevelopmental diseases and toxicity screening (PK/PD studies, hit-to-lead optimization, efficacy studies).
3D-BD
www.neurond.de
Added on: 11-21-2022
3D visualization of the brain using multiscan technology
CompanyEaglescience Software B.V., Amsterdam, Netherlands
Eaglescience B.V. works in collaboration with various companies and medical research centres in the development of AI-supported software (Neurostars) that enables personalized 3D visualization of the brain. By combining different neuroimaging and scanning technologies and using deep learning algorithms, the relevant tissue types (e.g. brain, veins, tumor) and patterns can be displayed in a differentiated manner. Using an easy-to-use software tool, the diverse information is synchronized and converted into a three-dimensional brain model of the patient in a virtual environment. The program uses additional lighting techniques to create shadows and reflections to enable realistic depth vision. This allows neurosurgeons to plan their procedures precisely and also train in a virtual reality environment. Furthermore, Neurostars improves doctor-patient communication by facilitating the shared decision-making process and patient approval for a recommended operation. By integrating the software platform into teaching, the program can help improve the training of brain surgeons and students. In summary, the Neurostars project can help advance neuroscience research, as well as create new opportunities to improve diagnosis and personalized treatment of patients with neurological diseases.
Neurostars. Virtuele 3D visualisatie van de hersenen
info@eaglescience.nl
Added on: 04-09-2024
AI-assisted (epi-)genetic screening platforms for toxicology and efficacy studies
CompanyToxGenSolutions B.V., Maastricht, Netherlands
The company ToxGenSolutions specializes in identifying drug targets and developing new drugs. The company's goal is to detect severe diseases (such as neurodegenerative diseases, cancer, (auto-)immune deficiencies) at an early stage and stop them in their tracks. Based on (epi)genetic data sets, computer tools identify potential drug candidates. For toxicity and efficacy evaluation, human spheroids are exposed to the active ingredient to be tested and subjected to high-throughput screening. The AI-based methods accelerate previous complex and time-consuming testing procedures. They also open up the possibility of developing personalized medicines. In addition to processes for developing and testing the safety and efficacy of new active ingredients, the company also develops various methodological tools to optimize early diagnostics. Currently, ToxGenSolutions is working to validate a diagnostic tool that will enable preclinical diagnosis of Alzheimer's disease with a focus on differences between men and women.
ToxGenSolutions
erwin.roggen@toxgensolutions.eu
Added on: 11-22-2023
Alzheimer's Disease model with de novo TAUopathies
CompanyNeuron-D GmbH, Dresden, Germany
To simulate the endogenous development of human neurons and mimic neurodegeneration processes, the company Neuron D has established novel 3D hydrogel cell cultures based on human neural stem cells.
The modular hydrogel system allows independent control of physical (stiffness, swelling) and biochemical properties (presentation of adhesion ligands and glycosaminoglycan-binding signalling molecules) as well as localized cell-regulated transformation via enzymatically cleavable peptide units.
Neural networks can be generated by incorporating human neural stem cells into the matrix. The function and morphology of the neurons correspond to human cortical neurons, as evidenced by matching molecular markers and electrophysiological functions.
In the 3D Alzheimer's model, the neural networks are used to simulate pathological changes, such as the amyloid toxicity known to occur in Alzheimer's disease. Consistent with clinical symptoms, the model results in neuronal cell death, loss of active synaptic connections and neuronal connectivity, decreased neural stem cell proliferation and neurogenesis, loss of neuronal marker expression in the cortices, and formation of TAU pathology.
3D-AD
info@neurond.de
Added on: 11-21-2022
Brain surgery simulator
CompanyCAE Healthcare, Sarasota, USA
The NeuroVR is a virtual reality training device for open cranial and endoscopic brain surgery. With modules that replicate realistic instruments, imaging, and open neurosurgical procedures, it allows a risk-free, self-directed practice. It features realistic sounds, realistic scope lens blurring and lifelike renderings of brain tissue, vessels and tumors. Modules for instrument handling are suction, ultrasonic aspirator, bipolar forceps and microscissors. Fundamental skills modules like burr hole selection, endoscopic ventricular landmarks, tumor debulking and aneurysm exposure are available. Endoscopic surgery modules include sphenoid ostium drilling, ethmoidectomy and endoscopic third ventriculostomy (ETV). Microsurgery for meningioma and glioma can be trained as well.
NeuroVR
www.caehealthcare.com
Added on: 03-30-2021
BrainSim: 3D in vitro model for drug and toxicology screening of the central nervous system
CompanyAxoSim, Inc., New Orleans, USA
AxoSim's BrainSim platform is an in vitro model that, when combined with an AI, enables improved toxicology and drug screening of the central nervous system. For this purpose, three-dimensional spheroids are cultivated based on inductive, pluripotent stem cells. These are then used in the BrainSim platform, where further differentiation generates three relevant, critical cell types (neurons, astrocytes and oligodendrocytes) of the central nervous system in a biomimetic environment. The cultivation method induces a high level of myelination and reflects important properties of the characteristic cells of the CNS and their interaction, and allows for an imaging of the brain structure. Reactions between the different cell types are characterized using electrophysiology, immunohistochemistry (ICC), histology, flow cytometry and gene expression. These can be accompanied by phenotypic changes in the mechanisms of action of the drugs to be tested. As a result, relevant predictive data is determined more quickly than is possible with the previous, established methods. The BrainSim platform thus enables the identification of neurotoxic substances and improves drug development and research into neurodegenerative diseases.
BrainSim®
info@axosim.com
Added on: 06-06-2023
CorePlate™: Cell culture with bidirectional multi-electrode arrays
Company3Brain AG, Pfäffikon, Switzerland
The CorePlate™ by 3Brain equips cell culture plates with bidirectional high-density multi-electrode arrays (HD-MEAs) for neuronal recording and stimulation. Each culture well integrates a custom BioSignal Processing Unit (BioSPU), which is a silicon-based processing core with thousands of sensors and actuators in a few square millimetres, to allow for real-time, high-resolution capture of all electrophysiological activity. The products support 2D (BioCAM) as well as 3D (HyperCam) environments suitable for neural cell cultures, brain slices, and 3D models. To further support cell health and experimental complexity, the systems include microfluidic options that provide precise control over cellular environments. Complementing this, the BrainWave software facilitates real-time data acquisition and analysis. 3Brain’s systems can be used in several fields, including basic neuroscience, disease modelling, drug discovery, as well as brain-computer interface research.
CorePlate™: Bringing deep tech to cell culture assays
contact.eu@3brain.com
Added on: 11-07-2024
DDI-Chips, investigation of cell interactions at different distances
CompanyInitio Cell, Leiden, Netherlands
Initio Cell develops patented multi-functional organ-on-a-chip devices and assays for drug discovery and diagnostics. The platforms can be used to create a microenvironment of the tumor, lung, gut, skin, brain and vasculature. The DDI (distance-dependent interaction) chip investigates the interactions between different cells as well as between cells and/or factors at different distances from each other. The physiological setup enables simultaneous investigations of different distances in the same device.
Initio Cell - A new discovery in every chip
info@initiocell.com
Added on: 12-21-2022
Development of 3D brain organoids to study neuronal plasticity
Companymyriamed GmbH, Goettingen, Germany
The biotechnologically engineered neuronal organoids (BENOs) from myriamed consist of excitatory (glutamatergic) and inhibitory (GABAergic) neurons, as well as supporting glial cells (astrocytes, oligodendrocytes). The stem cell-derived cells are cultivated in a collagen hydrogel in which they form highly interconnected, three-dimensional neural networks. Studies have shown that BENOs recapitulate important steps in fetal development of the human brain, such as the appearance of giant depolarizing potentials (GDPs). After more than 40 days in culture, a reduction in GDPs and a GABA polarity switch were observed, indicating progressive maturation of the mini brain models. After two months, an accelerated development and an increased occurrence of neuronal networks, as well as indications of long-term potentiation, could be observed. BENOs therefore enable a deeper investigation of the neuronal plasticity of the brain, as well as a modelling of neuronal diseases. The brain organoids are suitable for a variety of (pre-)clinical studies and can help to expand the understanding of the development and maturation processes of the brain and to improve drug development.
myrTissue-Brain
contact@myriamed.com
Added on: 08-16-2023
The Dividat Senso is a training device that helps people improve their cognitive and physical performance through exercise-based games. The platform consists of a screen with game software and a floor panel with four fields that measure steps, weight displacement and balance. The users attempt to complete a sequence of movements with their feet as indicated on the screen, enabling them to train both physical movement and cognitive function simultaneously. Training with this machine enhanced the cognitive skills of dementia patients, such as attention, concentration, memory and orientation.
hello@dividat.com
Added on: 05-11-2021
High throughput drug screening for neurodegenerative diseases
CompanyNeuron-D GmbH, Dresden, Germany
The Dresden-based start-up “Neuron-D GmbH” is developing a high-throughput system for testing drug candidates to treat neurodegenerative diseases. The technology is based on a 3D cell culture method, which replicates key features of neurons in the human brain and the pathology associated with neurodegeneration much better than conventional methods. The patented 3D brain model is customizable, cost-effective and delivers fast results. The approach is based on stem cells derived from healthy adults or patients and is aimed in particular at screening drugs against neurodegenerative diseases such as Alzheimer’s disease. The screening platform will be available in 2022.
Caghan Kizil
Added on: 05-11-2021
hiPSC-based neurons for modelling neurological diseases and assessing neurotoxicities
CompanyFUJIFILM Cellular Dynamics Inc., Madison, USA
The nerve cells from FUJIFILM Cellular Dynamics Inc. (FCDI) obtained from human induced pluripotent stem cells (hiPSCs) enable the development of complex, three-dimensional mini-brain models for researching neurological processes and diseases. The iCell kits include a range of different cell types such as: astrocytes, microglia, motor neurons, retinal pigment epithelial cells, various neurotransmitter-associated nerve cells (dopa, GABA and gluta neurons), as well as a specially developed cell kit for modeling the blood-brain barrier. The iCell Blood-Brain Barrier Isogen Kit is of particular relevance for drug research as it enables the evaluation of drugs to be tested with regard to possible neurotoxicities, as well as an assessment of their permeability and their possible influence on the barrier function of the blood-brain barrier. The cell kits are suitable for modelling different diseases of the central nervous system; ranging from neurodegenerative diseases, such as Parkinson's or Alzheimer's, to neurodevelopmental diseases, such as autism spectrum disorders (ASD). FCDI offers the cryopreserved nerve cells in a healthy state and with pre-programmed diseases. The neural iCell kits are therefore suitable for a variety of (pre-)clinical applications and studies and can help to expand the understanding of neuropathological processes and improve the drug therapy of neurological diseases.
iCell iPSC neurons
www.fujifilmcdi.com
Added on: 09-21-2023
hiPSC-derived cardiac and neuronal cell lines for drug screening and disease modelling
CompanyNcardia, Leiden, Netherlands
The company Ncardia specializes in the differentiation and development of human induced pluripotent stem cells (hiPSCs) into complex microtissues/microorgans. Ncardia currently offers a heart and a nerve cell line and is working on the serial development of other tissue types. The three-dimensional models can be tailored to the researchers' wishes in terms of their phenotypic characteristics. The cells are suitable for modelling various diseases and can be produced in large batches with low variability, enabling the development of assay-based high-throughput screenings. In addition to the two well-established cell lines, Ncardia offers the development of personalized models that are derived directly from samples from the patients being treated. This allows targeted drug research to be carried out. The company's modelling and screening technologies can help save time and costs when conducting drug trials and also promise further advances in the field of personalized medicine.
Integrated drug discovery services from Ncardia
support@ncardia.com
Added on: 10-04-2023
Human 3D cell spheres for toxicity testing in neurodevelopmental phase
CompanyDNTOX GmbH, Dusseldorf, Germany
The company DNTOX has developed the so-called Neurosphere Assay, which enables research into neurotoxic interactions of different neurological development phases and cell types. For this purpose, primary human neural progenitor cells are cultured into floating or plated, adherent three-dimensional spheres. Cell differentiation into characteristic cells of the central nervous system (neurons, astrocytes, oligodendrocytes) takes place over a period of 1 to 5 days, depending on the cell type. For the visualization and biomedical assessment of the cultured cells in the different migration phases, the cells are stained with TUBB3 and identified using computer-aided methods. Depending on the research interest, different neurotoxins and their pathological effects on cell proliferation, differentiation, connectivity and myelination of the central nervous system can be examined in different test series. For example, the effects of methylmercury poisoning on NPC migration or the pathocellular changes in Zika virus infection can be recapitulated. The multicellular assay allows for more in-depth exploration of a variety of embryonic and neonatal neurodevelopmental disorders and may help to improve understanding of cellular pathological processes and predictively identify neurotoxic interactions of drugs and other agents on the developing nervous system.
Developmental Neurotoxicity (DNT) Testing
info@dntox.de
Added on: 07-04-2023
IC-Chips, assessing cell invasion and chemotaxis using organ-on-a-chip
CompanyInitio Cell, Leiden, Netherlands
Initio Cell develops patented multi-functional organ-on-a-chip devices and assays for drug discovery and diagnostics. The platforms can be used to create a microenvironment of the tumor, lung, gut, skin, brain and vasculature. The IC (Invasion Chemotaxis) chip provides an easy-to-use and physiologically relevant microenvironment to directly visualize and quantitatively assess migration and invasion of cells with high temporal and spatial resolution. The IC chip also provides the main platform for mimicking various organs.
Initio Cell - A new discovery in every chip
info@initiocell.com
Added on: 12-21-2022
Identification of new biomarkers for cancer and neurodegenerative diseases
CompanyVITO NV, Mol, Belgium
Biomarkers are used in prevention, screening for certain diseases and evaluating treatments. The VITO organization focuses on the identification of biomarkers for minimally invasive diagnostic applications, preferably using liquid biopsies (urine, blood and cerebrospinal fluid). In addition, however, fresh and fixed tissue material is also used for biomarker development using MALDI-based imaging. Within the scope of biomarker research, VITO focuses on the following areas:
1. Mainly for cancer research (bladder and lung cancer) and neurodegenerative diseases (dementia), VITO uses state-of-the-art mass spectrometry for the identification and detection of (panels of) protein biomarkers.
2. In the context of cancer research (especially lung and colorectal cancer), immunopeptides are analysed using immunopeptidomics with regard to applications in T-cell therapy, immunotherapy and personalised vaccination.
www.vito.be
Added on: 11-19-2021
Lab-on-chip technology for migration assays and mechanobiological studies
CompanyCompreVie GmbH, Vienna, Austria
The CompreChip from CompreVie is based on a microfluidic lab-on-chip technology that enables controlled and fully automated (long-term) stimulation or wounding of different types of microtissue. A pneumatic system applies pressure to the cells cultivated in microchannels via a flexible membrane integrated into the chip. This allows different forms of mechanical stress, tissue injuries and trauma to be simulated. To analyse cellular processes, the platform is compatible with all common image analysis systems. One chip can be used to carry out up to 8 test series. The platform is suitable for a variety of different studies, ranging from cell migration studies to assess invasive substances to research into brain trauma or skin regeneration processes, making it a helpful and versatile tool for human-based in vitro research.
CompreChip
info@comprevie.com
Added on: 09-13-2023
microBrain from StemoniX for high-throughput analyses
CompanyStemoniX, Maple Grove, USA
StemoniX’s microOrgan plates contain ready-to-use functional microtissues engineered from human induced pluripotent stem cells (iPSC). The microOrgans are designed to enable high-throughput human drug screening without the need for drugs to enter a human body. Containing a physiologic mixture of neurons and astrocytes co-matured from a single donor source, cells in the StemoniX microBrain platforms express key markers of cell maturity and a high density of key neural synapses. microBrain 3D cortical spheroids present quantifiable, robust and uniform spontaneous and synchronized calcium oscillations that can be measured in kinetic high-throughput plate readers and high content imaging systems. microBrain 2D cultures, also high-throughput, are ideal for imaging and infection studies.
info@stemonix.com
Added on: 03-24-2022
Microelectrode array and live cell analysis systems for assay-based studies
CompanyAxion BioSystems, Inc., Atlanta, USA
Axion BioSystems microelectrode array (MEA) and live cell analysis systems (Maestro Edge and Maestro Pro) enable non-invasive, label-free measurement and visualization of cellular activities in real time. The models detect important parameters of neuronal network activity, cardiac function, and cell growth, death, and adhesion. Integrated software programs enable precise control and monitoring of the cultured microtissues. The CO2 and temperature ratio of the cell environment is regulated via “smart environment chambers”. The control of cell activity occurs through electrical stimulation or light pulses via the compatible Lumos optical stimulation system. To further fine-tune the experiments, the company offers a range of different opaque and transparent MEA cell culture plates in various well-size formats, which are equipped with low-noise recording electrodes and special stimulation electrodes. Using a “one-button setup”, the experiments can be fully automated over a period of up to several weeks and can be controlled and monitored independently of the laboratory via a compatible smartphone app. The models are suitable for neuro-, cardio- or oncological screening procedures to identify relevant active ingredients, as well as for the analysis of virological processes or the assessment of short-term and long-term cellular interactions. The Maestro systems enable the development of a variety of different assay-based studies that can help deepen the understanding of pathological processes and accelerate the target validation of promising drug candidates in drug development.
MEA
www.axionbiosystems.com
Added on: 09-06-2023
Microfluidic neuron-on-chip models for drug and drug discovery
CompanyNETRI, Lyon, France
The company NETRI has developed the Neuro-FluidicsTM Line for improved target validation and drug development against neurological diseases. The product line includes 6 Neuron-on-Chip platforms with 4 different architecture types. The microfluidic models combine two different technologies in a single chip and enable controlled cultivation of 2-3 co-cultures in separate compartments. All products are based on the so-called NeoBento technology, a 96-well microculture plate that is compatible with common liquid handling devices and imaging processes. 3 models (DuaLink, DuaLink Shift and TriaLink) are combined with a special micro-tunnel technology that allows for improved fluidic isolation and discontinuous connectivity between cell compartments. The other three chip models (DuaLink Ultra, TriaLink Ultra, and DuaLink Delta Ultra) have integrated microgroove technology that achieves improved axonal projection rate and continuous connectivity between co-cultures. The neuron-on-chip models are suitable for a variety of different preclinical studies and can help to expand the understanding of neuronal activities and their interactions in health and disease.
NeuroFluidics™ Line
contact@netri.com
Added on: 08-29-2023
Midbrain organoids for modeling and research in Parkinson's disease
CompanyOrgano Therapeutics, Esch-sur-Alzette, Luxembourg
The company Organo Therapeutics has specialized in the development of brain organoids for research into Parkinson's disease. The models recapitulate important functional and structural properties and express relevant midbrain markers (LMX1 and FOXA2). Organoids derived from tissue samples from healthy donors show a high number of neurons (dopaminergic, glutamatergic, GABAergic) and astrocytes. Organoids obtained from samples from Parkinson's patients show an impairment in neuronal dopamine production following the clinical picture. The company uses various AI-based screening methods to analyse and evaluate the cellular processes. The midbrain organoids have been shown to be useful in modelling Parkinson's and may help advance understanding of pathological processes and improve drug development.
Human midbrain organoids
jens.schwamborn@organo-therapeutics.com
Added on: 08-22-2023
Nano-lab-on-the-chip technology with mini brains
CompanyNORGANOID, Graz, Austria
NORGANOID build on the latest developments in human stem cell technology, fluidic bio-reactors and nanosensors, generating a system to engineer brain tissues directly from the patient’s stem cells for modelling brain degeneration such as in Parkinson´s disease, Alzheimer´s disease or epilepsy. Moreover, it supports the execution and analysis of drug tests in real-time. The method uses nano-lab-on-a-chip technology, an optimized platform of the organ-on-a-chip system and features rapidly emerging 3D brain organoids, real-time drug testing, a high degree of accuracy and complete scalability.
Turnkey brain-on-chip-solution
Charlotte Ohonin
Added on: 03-18-2021
NerveSim: 3D in vitro model for drug and toxicology screening of the peripheral nervous system
CompanyAxoSim, Inc., New Orleans, USA
AxoSim's NerveSim platform is an in vitro model that, when combined with an AI, enables improved toxicology and drug screening of the peripheral nervous system. For this purpose, three-dimensional spheroids are cultivated from induced pluripotent stem cells (iPSCs). These are then inserted into the NerveSim platform and further grown into a biomimetic model that mimics the form and function of peripheral nerves. The model features unique Schwann cell myelination and reliably produces key clinical measures (nerve excitability, conduction, and histomorphometry) of peripheral neuropathies and neuropathic pain previously only achievable in in vivo clinical methods. The SimTox platform, for the detection of neurotoxic agents, has a higher sensitivity to neurotoxic agents compared to the currently established clinical models, thereby enabling faster treatment to save the patient. With the SimDiscovery platform, neurological clinical pictures can be simulated and drugs in the development phase can be identified safely and faster than is possible with previous time-consuming and cost-intensive methods. The NerveSim platform thus enables more targeted treatment of patients and is proving to be suitable for improving long-awaited drug development.
NerveSim®
info@axosim.com
Added on: 05-30-2023
Neuron-on-Chip with integrated microelectrodes for research into neurological diseases
CompanyNETRI, Lyon, France
NETRI's NeuroFluidics MEA line was developed in cooperation with Axion Biosystems and combines organ-on-chip platforms with multi-electrode array technology. This enables the electrophysiological recording of microfluidic experiments. The DuaLink MEA and TriaLink MEA platforms are specifically designed for modelling isolated co-cultures linked via axons and functional activity recording. DuaLink Shift MEA enables synaptic isolation and functional activity recording. This allows the individual cell cultures to be modelled and evaluated independently of one another. The product line is based on specially developed cell culture plates (NeoBento), which are available with 16 chips (and 768 electrodes) or 8 chips (and 384 electrodes). The platforms are compatible with common standard models for additional (liquid) treatments or imaging procedures. The neuron-on-chip models are suitable for carrying out (high-throughput) screenings of certain active substances and can help to improve the research and drug treatment of neurological diseases such as Alzheimer's or peripheral neuropathic pain.
NeuroFluidics™ MEA Line
contact@netri.com
Added on: 08-22-2023
Personalised brain maps to optimize the diagnosis and treatment of brain tumor
CompanyBraincarta, Utrecht, Netherlands
In order to be able to use the advantages of functional MRI scan technology for the diagnosis and treatment planning of brain tumor patients in smaller clinics and oncological therapy facilities, the company Braincarta has developed the Elonav concept. Elonav is an AI-powered, fully automated data processing and evaluation program that enables functional MRI scans to be performed without the presence of a specially trained technical expert. The patient's fMRI data is recorded according to standardized specifications and then uploaded to the Braincarta server. To evaluate brain function and structure, the recorded patient data is compared with an integrated patient database. Based on this comparison and using well-known neurologically relevant algorithms, Elonav creates a personalized brain map of the patient, which provides doctors with precise information about the location of the tumor as well as the structure and functionality of neighbouring brain areas. Within a few hours, the data protection-compliant results are provided in the form of a PDF report and a 3D DICOM file. The three-dimensional, image representation of the brain enables neurosurgeons and radiation therapists to develop a targeted and personalized treatment strategy. In summary, the CE-certified method proves to be an innovative digital solution that can help make fMRI technology accessible to all patients for optimal medical care and reduce possible treatment risks (such as functional damage caused by neurosurgical procedures or radiation). Additionally, the Elonav concept is suitable for multicentre pharmaceutical and biotechnology research projects that require standardized protocols for fMRI, resting state fMRI and DTI (diffusion tensor imaging).
Personalised brainmaps
info@braincarta.com
Added on: 02-01-2024
Personalized electrical stimulation helmet for the treatment of degenerative brain diseases
CompanyBottneuro AG, Basel, Switzerland
To monitor and treat patients with neurodegenerative and neurological diseases, Bottneuro has specialized in the development of tailor-made tES (transcranial electrical stimulation) and EEG (electroencephalography) caps. Based on MRI data and information about the patient's head anatomy, the company creates a therapy plan and determines the individual positioning of the electrodes within the cap. The 3D printed helmets are equipped with up to 34 electrode channels, enabling targeted, non-invasive stimulation of selected brain areas. In addition to tES, the neurostimulation device is suitable for monitoring brain activity using EEG data. Through repeated recordings, subtle changes in the brain can be observed over time, the development of the disease can be traced, and the patient's response to tES can be evaluated. The implementation of the therapy sessions and/or the EEG measurements is controlled by the patient using an Android tablet. An integrated administration program allows physicians to view EEG and stimulation recordings via a secure server and access monthly session reports. tES shows high potential in the treatment of various physiological and psychological diseases such as Alzheimer's, Parkinson's, epilepsy, brain trauma, depression or addictions. In summary, the portable neurostimulation devices and therapy caps enable a new form of home medical care. Relevant treatments can be carried out independently by the patient comfortably and easily from home, thereby promoting patient compliance. The tES and EEG caps are also suitable for monitoring high-risk patients and can help to detect neurological and neurodegenerative diseases at an early stage using digital biomarkers.
Custom made, personalized tES and EEG caps
mail@bottneuro.ch
Added on: 04-23-2024
RealSpine: surgical spine model
CompanyRealists Training Technologies GmbH, Leipzig, Germany
RealSpine is a visually and haptically highly realistic training system for spine surgery. Microsurgical lumbar interventions can also be trained, as well as planning an operative strategy. Lifelike and accurate anatomy allows realistic lateral access, ATP (Anterior to Psoas) and transpsoas approach. Real patient cases make this portable training model a valuable educational device. The inner anatomical modules are easily replaceable. The radiolucent model is compatible with X-ray and fluoroscopy.
RealSpine
contact@realists.de
Added on: 12-02-2022
Vasularized Micro-Brain Platform
CompanyAracari Biosciences, Irvine, USA
When treating patients, most therapeutics are delivered through the blood vessels. In Aracari’s platforms, self-assembled human blood vessels not only support tissue growth through delivery of nutrients, but also deliver drugs and cell therapies. The Vascularized Micro-Brain platform is designed to test therapeutic permeability across the blood-brain barrier. The system includes human endothelial cells, human stromal and glial cells, and enrichment of blood-brain barrier genes. Further services include physiological delivery of drugs across the barrier, tissue toxicities in the brain stromal compartment, tissue extraction for qRT-PCR and bulk or single-cell RNA seq. Aracari’s vascularized microphysiological systems provide relevant, physiological data for accelerating drug development.
Vascularized micro-brain (VMB™)
info@aracaribio.com
Added on: 12-19-2022
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