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
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