Protection against amyloid beta peptide toxicity by zinc

Abstract

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 (Aβ), the major component of senile plaques in Alzheimer's disease (AD). This study reports the effect of varying Zn concentrations on Aβ toxicity and the mechanism by which low concentrations function in a protective role. At Aβ/Zn molar ratios of 1:0.1 and 1:0.01, Zn produces significant protection against Aβ toxicity in cultured primary hippocampal neurons. At higher concentrations (1:1 molar ratio), Zn offers no protection or enhances Aβ toxicity. The protective effect of Zn against Aβ 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 Aβ 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 Aβ (50 μM), Zn at concentrations of 5 and 0.5 μM led to significant increases in Na +/K + ATPase activity compared with levels in cells treated with Aβ alone. Zn at a 1:1 molar ratio (50 μM) led to a significant decrease in enzyme activity. Together, these data suggest that Zn functions as a double-edged sword, affording protection against Aβ at low concentrations and enhancing toxicity at high concentrations.