Effect of zinc ions on the cytotoxicity induced by the amyloid beta-peptide.
Insoluble aggregates of the amyloid beta-peptide (A beta) are a major constituent of senile plaques found in brains of Alzheimer's disease patients. The beta-amyloid fragment A beta(1-40) is toxic to rat pheochromocytoma PC12 cells, leading to a concentration-dependent decrease in the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The detrimental effects of A beta(1-40) are enhanced in the presence of 1 mM zinc, whereas 50 microM zinc exerts a protective effect against A beta(1-40)-induced toxicity. Exposure of PC12 cells to low zinc concentrations (50 microM) affords a decrease (1.4-fold) in the extent of lipid peroxidation, a decrement in protein oxidation (1.1-fold), and an increase in ATP levels (1.2-fold), although the differences were not statistically significant. However, treatment of cells with high concentrations of zinc (1 mM) led to significant increases in lipid peroxidation (3.7-fold) and protein oxidation (1.5-fold) and to depletion of the ATP pool (21-fold). These data suggest that zinc has a concentration-dependent dual effect, protective and toxic, thus playing an important role in the pathogenesis of Alzheimer's disease.
Center for Neuroscience of Coimbra, Faculty of Medicine and Department of Zoology, University of Coimbra, Portugal.
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002244:Carbon / Q000378:metabolism; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007477:Ions; D015227:Lipid Peroxidation / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D015032:Zinc / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D007477:Ions; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D002244:Carbon; D000255:Adenosine Triphosphate; D015032:Zinc; D010100:Oxygen