Protection against amyloid beta peptide toxicity by zinc

Zinc (Zn) is an essential element in normal development and biology, although it is toxic at high concentrations. Recent studies show that Zn at high concentrations accelerates aggregation of amyloid beta peptide (A beta), the major component of senile plaques in Alzheimer's disease (AD). This study reports the effect of varying Zn; concentrations on A beta toxicity and the mechanism by which low concentrations function in a protective role. At A beta/Zn molar ratios of 1:0.1 and 1:0.01, Zn produces significant protection against A beta toxicity in cultured primary hippocampal neurons. At higher concentrations(1:1 molar ratio), Zn offers no protection or enhances A beta toxicity. The protective effect of Zn against A beta toxicity is due in part to the enhancement of Na+/K+ ATPase activity which prevents the disruption of calcium homeostasis and cell death associated with A beta toxicity. Analysis of Na+/K+ ATPase activity in cultured rat cortical cells indicated that Zn exposure alone afforded a 20% increase in enzyme activity, although the differences were statistically insignificant. However, in cortical cultures exposed to a toxic dose of A beta (50 mu M), Zn at concentrations of 5 and 0.5 mu M led to significant increases in Na+/K+ ATPase activity compared with levels in cells treated with A beta alone. Zn at a 1:1 molar ratio (50 mu M) led to a significant decrease in enzyme activity. Together, these data suggest that Zn functions as a double-edged sword, affording protection against A beta at low concentrations and enhancing toxicity at high concentrations. (C) 1999 Elsevier Science B.V. All rights reserved.