Effect of Zinc Ions on the Cytotoxicity Induced by the Amyloid β -Peptide

Abstract

Insoluble aggregates of the amyloid β-peptide (Aβ) are a major constituent of senile plaques found in brains of Alzheimer's disease patients. The β-amyloid fragment Aβ _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 Aβ _1–40 are enhanced in the presence of 1 mM zinc, whereas 50 μM zinc exerts a protective effect against Aβ _1–40-induced toxicity. Exposure of PC12 cells to low zinc concentrations (50 μM) 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.