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

β-Amyloid (Aβ) 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 Aβ-membrane interactions in the mechanism of Aβ neurotoxicity and indicates that cholesterol and gangliosides are particularly important for Aβ aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on Aβ-induced GTPase activity in cells, a step implicated in the mechanism of Aβ toxicity, and Aβ-induced cell toxicity. Cholesterol reduction and depletion of membrane-associated sialic acid residues both significantly reduced the Aβ-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from Aβ-induced toxicity. These results indicate the importance of Aβ-membrane interactions in the mechanism of Aβ 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.