Reduction in cholesterol and sialic acid content protects cells from the toxic effects of beta-amyloid peptides.
beta-Amyloid (Abeta) 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 Abeta-membrane interactions in the mechanism of Abeta neurotoxicity and indicates that cholesterol and gangliosides are particularly important for Abeta aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on Abeta-induced GTPase activity in cells, a step implicated in the mechanism of Abeta toxicity, and Abeta-induced cell toxicity. Cholesterol reduction and depletion of membrane-associated sialic acid residues both significantly reduced the Abeta-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from Abeta-induced toxicity. These results indicate the importance of Abeta-membrane interactions in the mechanism of Abeta 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.
Wang
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Department of Chemical Engineering, Texas A & M University, College Station, Texas 77843-3122, USA.
Rymer
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Good
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D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002784:Cholesterol / Q000032:analysis*; D019610:Cytoprotection; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005732:Gangliosides / Q000032:analysis; D006801:Humans; D019158:N-Acetylneuraminic Acid / Q000032:analysis*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D051381:Rats; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D013778:Tetrazolium Salts; D013844:Thiazoles; D002784:Cholesterol; D020558:GTP Phosphohydrolases; C022616:thiazolyl blue; D019158:N-Acetylneuraminic Acid