抄録
Cholesterol has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the underlying mechanisms are not yet clear, several studies have provided evidence for the involvement of cholesterol-rich lipid rafts in the production of amyloid β peptide (Aβ), the major component of amyloid deposits in AD. Lipid rafts are membrane microdomains enriched in cholesterol and sphingolipids, and proteins can be selectively included or excluded from these microdomains. Lipid rafts have been shown to function as a concentrating platform for a variety of signal transduction molecules. Aβ is generated by two sequential proteolytic cleavage steps from the β-amyloid precursor protein (βAPP). βAPP is initially cleaved by β-secretase, which has been identified as a β-site APP-cleaving enzyme (BACE), followed by the subsequent intramembrane proteolysis of the membrane-bound C-terminal fragment (βCTF, C99) catalyzed by γ-secretase. Recent reports have suggested that β- and γ-secretase are localized in lipid rafts and cholesterol can regulate these activities or distributions. These data demonstrated that lipid rafts offer a structural platform for examining cholesterol’s effect on Aβ generation. The association of the Aβ-producing enzyme with lipid rafts and its relation to cholesterol metabolism will provide new insights for understanding the mechanism of Aβ generation in AD.
