Plasma membrane injury depends on bilayer lipid composition in Alzheimer's disease

Increasing evidence indicates that interaction of amyloid-β peptide (Aβ) 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 Aβ production, aggregation, and interaction with the cell membrane. In this study we show that Aβ42 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 Aβ42 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.