Zinc lowers amyloid-β toxicity by selectively precipitating aggregation intermediates

Abstract

Soluble amyloid-β (Aβ) aggregates are suspected to play a major role in Alzheimer's disease. Zn²⁺ at a concentration of a few micromolar, which is too dilute to affect the precipitation equilibrium of Aβ, can destabilize these aggregates [Garai, K., Sengupta, P., Sahoo, B., and Maiti, S. (2006) Biochem. Biophys. Res. Commun. 345, 210−215]. Here we investigate the nature of these aggregates in the context of the precipitation pathway, the mechanism underlying their destabilization, and the biological consequences of this destabilization. We show that the larger soluble aggregates (size >10 nm) form only in supersaturated Aβ solutions, implying that they are intermediates in the pathway toward fibril formation. We also show that Zn²⁺ destabilizes these intermediates by accelerating their aggregation kinetics. The resulting change in the size distribution of the Aβ solution is sufficient to eliminate its toxicity to cultured mammalian neurons. Our results provide an explanation for the existing observations that Zn²⁺ at a concentration of a few micromolar significantly reduces Aβ toxicity.