engleski

Amyloid-β : from molecular biology to clinical practice

Altered processing of the β -amyloid precursor protein (APP) leading to increased formation of amyloid-β peptide (Aβ ) is considered to be a central event in the pathogenesis of Alzheimer’ s disease (AD). Understanding the mechanism of Aβ formation is crucial for developing novel therapies for AD as well as for understanding normal APP function. The goal of our research is to elucidate the molecular and cellular pathways of Aβ production and to investigate whether analyzing the levels of Aβ peptide in the cerebrospinal fluid (CSF) may be considered for differential diagnosis of Alzheimer’ s disease. Using NPC disease as a model to study cholesterol-effect on Aβ , we found that increased cholesterol levels lead to markedly increased levels of Aβ (ELISA Aβ , BioSource Int. Inc.). A fluorescent-based assay revealed that this effect was not due to increased activities of β - and/or γ -secretase, the two enzyme activities that are crucial for Aβ formation. In addition, by confocal microscopy and by lipid raft isolation in a sucrose discontinuous gradient we show that cholesterol accumulation does not lead to increased compartmentalization of APP in lipid rafts, a membrane microdomains rich in cholesterol and shingolipids previously found to be the site of Aβ synthesis. Indeed, we observed that cholesterol overload in NPC1-null cells leads to altered trafficking of APP within endocytic compartments, supporting that increased distribution of APP within early/late endosomes leads to increased Aβ production. Using an ELISA CSF assay (Innogenetics) we found that the levels of Aβ 42 in the CSF of AD individuals were markedly decreased compared to its levels in the CSF of non-AD and control subjects. Our results support that cholesterol levels modulate the levels of Aβ by an indirect mechanism, indicating that regulating cholesterol levels (using statins/cholesterol lowering drugs) may be considered to treat, prevent or decrease the progression of Alzheimer’ s disease. Indeed, clinical trials on the use of statins for treating AD are currently under investigation. Together with emerging imaging tools of Aβ in the brain, analysis of the CSF Aβ 42, tau and phosho181-tau levels may be considered for differential diagnosis of Alzheimer’ s disease.

Alzheimer's disease; cholesterol; APP protein; Abeta peptide; neurodegeneration

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