Effect of zinc ions on the cytotoxicity induced by the amyloid beta-peptide.

Abstract

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.