Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of £]-Amyloid Peptides

£]-Amyloid (A£]) is the primary protein component of senile plaques associated with Alzheimer's disease and has been implicated in the neurotoxicity associated with the disease. A variety of evidence points to the importance of A£]-membrane interactions in the mechanism of A£] neurotoxicity and indicates that cholesterol and gangliosides are particularly important for A£] aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on A£]-induced GTPase activity in cells, a step implicated in the mechanism of A£] toxicity, and A£]-induced cell toxicity. Cholesterol reduction and depletion of membrane-associated sialic acid residues both significantly reduced the A£]-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from A£]-induced toxicity. These results indicate the importance of A£]-membrane interactions in the mechanism of A£] toxicity. In addition, these results suggest that control of cellular cholesterol and/or ganglioside content may prove useful in the prevention or treatment of Alzheimer's disease.