Journal
AGING CELL
Volume 10, Issue 3, Pages 403-417Publisher
WILEY
DOI: 10.1111/j.1474-9726.2011.00681.x
Keywords
cholesterol; Alzheimer's disease; oxysterols; amyloid-beta; oxidative stress; neurotoxicity
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Funding
- European Science Foundation
- Italian Ministry of University
- Prin
- Piedmontese Regional Government
- CRT Foundation, Turin
- University of Turin, Italy
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P>All three cholesterol oxidation products implicated thus far in the pathogenesis of Alzheimer's disease, 7 beta-hydroxycholesterol, 24-hydroxycholesterol, and 27-hydroxycholesterol, markedly enhance the binding of amyloid-beta (A beta) to human differentiated neuronal cell lines (SK-N-BE and NT-2) by up-regulating net expression and synthesis of CD36 and beta 1-integrin receptors. However, only 24-hydroxycholesterol markedly potentiates the pro-apoptotic and pro-necrogenic effects of A beta(1-42) peptide on these cells: 7 beta-hydroxycholesterol and 27-hydroxycholesterol, like unoxidized cholesterol, show no potentiating effect. This peculiar behavior of 24-hydroxycholesterol at physiologic concentrations (1 mu m) depends on its strong enhancement of the intracellular generation of NADPH oxidase-dependent reactive oxygen species (ROS), mainly H2O2, and the consequent impairment of neuronal cell redox equilibrium, measured in terms of the GSSG/GSH ratio. Cell incubation with antioxidants quercetin or genistein prevents 24-hydroxycholesterol's pro-oxidant effect and potentiation of A beta-induced necrosis and apoptosis. Thus, the presence of 24-hydroxycholesterol in the close vicinity of amyloid plaques appears to enhance the adhesion of large amounts of A beta to the plasma membrane of neurons and then to amplify the neurotoxic action of A beta by locally increasing ROS steady-state levels. This report further supports a primary involvement of altered brain cholesterol metabolism in the complex pathogenesis of Alzheimer's disease.
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