The effect of Cu2+ and Zn2+ on the A beta(42) peptide aggregation and cellular toxicity

The coordination chemistry of Cu and Zn metal ions with the amyloid beta (A beta) peptides has attracted a lot of attention in recent years due to its implications in Alzheimer's disease. A number of reports indicate that Cu and Zn have profound effects on A beta aggregation. However, the impact of these metal ions on A beta oligomerization and fibrillization is still not well understood, especially for the more rapidly aggregating and more neurotoxic A beta(42) peptide. Here we report the effect of Cu2+ and Zn2+ on A beta(42) oligomerization and aggregation using a series of methods such as Thioflavin T (ThT) fluorescence, native gel and Western blotting, transmission electron microscopy (TEM), and cellular toxicity studies. Our studies suggest that both Cu2+ and Zn2+ ions inhibit A beta(42) fibrillization. While presence of Cu2+ stabilizes A beta(42) oligomers, Zn2+ leads to formation of amorphous, non-fibrillar aggregates. The effects of temperature, buffer, and metal ion concentration and stoichiometry were also studied. Interestingly, while Cu2+ increases the A beta(42)-induced cell toxicity, Zn2+ causes a significant decrease in A beta(42) neurotoxicity. While previous reports have indicated that Cu2+ can disrupt beta-sheets and lead to nonfibrillar A beta aggregates, the neurotoxic consequences were not investigated in detail. The data presented herein including cellular toxicity studies strongly suggest that Cu2+ increases the neurotoxicity of A beta(42) due to stabilization of soluble A beta(42) oligomers.