Non Animal Testing Database

Oversupply of cholesterol to APOE4 astrocytes leads to amyloidosis in human neurons

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
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