Amyloid cytotoxicity depends on membrane lipid composition in Alzheimer's disease

Lipid rafts microdomains act as critical pathological platforms for the toxic signaling pathways that underlie synaptic dysfunction and neuropathology in Alzheimer’s disease (AD). In particular, it has been demonstrated that lipid rafts are key sites of Aβ production, aggregation and interaction at the cell membrane. Different cell susceptibility to toxic amyloid aggregates of familial AD (FAD) fibroblasts depends on their ability to accumulate the amyloid assemblies onto the plasma membrane. Here we analysed the ability of lipid rafts to bind Aβ42 prefibrillar aggregates in relation to membrane cholesterol content in primary cultures of skin fibroblasts from FAD patients bearing APPVal717Ile, PS-1Leu392Val or PS-1Met146Leu gene mutations, as well as age-matched healthy subjects. We found that a moderate enrichment in membrane cholesterol reduces amyloid binding to lipid rafts, preventing the increase in cytosolic free Ca2+ and membrane permeabilisation triggered by Aβ42 in FAD fibroblasts. 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 permeabilisation. In primary rat cortical neurons and human SH-SY5Y neuroblastoma cells, mild cholesterol enrichment also prevented Aβ42-induced membrane permeabilisation, while cholesterol depletion enhanced this permeabilising effect, corroborating our hypothesis in a neuronal system. Overall, this data suggests that plasma membrane injury depends on lipid raft composition in Alzheimer’s disease.