Abstract
BackgroundOxidative stress is thought to be a key player in the pathogenesis of neurodegenerative dementia, including Alzheimer’s disease (AD). It has been assumed that oxidative stress contributes to the ß-amyloid deposition in cerebral blood vessels.MethodsIn order to prove this hypothesis, we examined the effect of oxidative stress on the processing of amyloid precursor protein (APP) in primary endothelial cells (EC) derived from cerebral cortical tissue of transgenic Tg2576 mice. Following exposure of EC by 1 μM hydrogen peroxide for up to 48 hours, formation and secretion of APP cleavage products sAPPα and sAPPß into the culture medium as well as the expression of endothelial APP were assessed.ResultsOxidative stress resulted in enhanced secretion of sAPPß into the culture medium as compared to controls (absence of hydrogen peroxide), which was accompanied by an increased APP expression, induction of VEGF synthesis, nitric oxide and oxygen free radicals productions, and differential changes of endothelial phospo-p42/44 MAPK expression.ConclusionThe data suggest that oxidative stress may represent a major risk factor in causing Aß deposition in the brain vascular system by initiating the amyloidogenic route of endothelial APP processing. The enhanced β-secretase activity following oxidative stress exposure, possibly promoted by phosphorylation of p42/44 MAPK.
Highlights
During the last decades a vast number of studies provided evidence that increased levels of oxidative stress occurs in conditions of neurodegeneration and even during brain aging
Oxidative stress resulted in enhanced secretion of sAPPß into the culture medium as compared to controls, which was accompanied by an increased amyloid precursor protein (APP) expression, induction of VEGF synthesis, nitric oxide and oxygen free radicals productions, and differential changes of endothelial phospo-p42/44 MAPK expression
To reveal whether oxidative stress affects the metabolism of APP, endothelial cells (EC) were exposed by hydrogen peroxide
Summary
During the last decades a vast number of studies provided evidence that increased levels of oxidative stress occurs in conditions of neurodegeneration and even during brain aging (for reviews, see e.g., [1, 2]). In neurological disorders such as multiple sclerosis, stroke, neuroinfection as well as neurodegenerative diseases, including Alzheimer’s disease, oxidative stress is thought to be a principal player and an early event that trigger the progression of the pathogenic mechanisms.
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