Plasma Membrane Injury Depends on Bilayer Lipid Composition in Alzheimer's Disease

Increasing evidence indicates that interaction of amyloid-beta peptide (A beta) with the cell membrane is a primary step in Alzheimer's disease (AD) neurotoxicity. In particular, it has been demonstrated that lipid rafts are key sites of A beta production, aggregation, and interaction with the cell membrane. In this study we show that A beta(42) oligomers are recruited to lipid rafts, leading to plasma membrane perturbation and Ca2+ dyshomeostasis in primary fibroblasts from familial AD patients bearing APPVal717Ile, PS-1Leu392Val, or PS-1Met146Leu gene mutations. In contrast, a moderate increase in membrane cholesterol content precluded the interaction of A beta(42) oligomers with the plasma membrane and resulting cell damage. Moreover, the recruitment of amyloid assemblies to lipid raft domains of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper increase in intracellular Ca2+ levels and plasma membrane permeabilization. Our findings suggest a protective role for raft cholesterol against amyloid toxicity in AD.