Membrane cholesterol content plays a key role in the neurotoxicity of β-amyloid: implications for Alzheimer's disease

Beta amyloid (beta A) plays a central role in the pathogenesis of the most common and devastating neurodegenerative disorder, Alzheimer's disease (AD). The mechanisms of beta A neurotoxicity remain controversial, but include dysregulation of calcium homeostasis and oxidative stress. A large body of data suggest that cholesterol plays a significant role in AD. In mixed cultures containing hippocampal neurons and astrocytes, we have shown that neurotoxic beta A peptides (1-42 and 25-35) cause sporadic cytosolic calcium ([Ca(2+)](c)) signals in astrocytes but not in neurons, initiating a cascade that ends in neuronal death. We now show, using the cholesterol-sensitive fluorescent probe, Filipin, that membrane cholesterol is significantly higher in astrocytes than in neurons and mediates the selective response of astrocytes to beta A. Thus, lowering [cholesterol] using mevastatin, methyl-beta-cyclodextrin or filipin prevented the beta A-induced [Ca(2+)](c) signals, while increased membrane [cholesterol] increased beta A-induced [Ca(2+)](c) signals in both neurons and astrocytes. Addition of beta A to lipid bilayers caused the appearance of a conductance that was significantly higher in membranes containing cholesterol. Increasing membrane [cholesterol] significantly increased beta A-induced neuronal and astrocytic death. We conclude that a high membrane [cholesterol] promotes beta A incorporation into membranes and increased [Ca(2+)](c) leading to cell death.