The involvement of lipid rafts in Alzheimer's disease

The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology involving a membrane-bound substrate metabolized by integral membrane proteases (secretases). Thus, the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients, is derived by sequential proteolytic cleavage of the integral transmembrane amyloid precursor protein (APP). Beta-Secretase or BACE-1 (beta-site APP cleaving enzyme) is a transmembrane aspartic protease responsible for the first of these cleavage events, generating the soluble APP ectodomain sAPPbeta, and a C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by the ?gamma-secretase complex, of which presenilin is the catalytic core, to produce Ass. A variety of studies indicate that cholesterol is an important factor in the regulation of Ass production, with high cholesterol levels being linked to increased Ass generation and deposition. However, the mechanism(s) underlying this effect are unclear at present. Recent evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Rafts may be involved in the aggregation of Ass and also in its clearance by amyloid-degrading enzymes such as plasmin or possibly neprilysin (NEP).