Inhibitory Effect of Copper(II) on Zinc(II)-Induced Aggregation of Amyloid β-Peptide

Abstract

Aggregation of amyloid β-peptide (Aβ), a key pathological event in Alzheimer's disease, has been shown in vitro to be profoundly promoted by Zn(II). This fact suggests that some factors in the normal brain protect Aβ from the Zn(II)-induced aggregation. We demonstrate for the first time that Cu(II) effectively inhibits the Aβ aggregation by competing with Zn(II) for histidine residues. The Raman spectrum of a metal–Aβ complex in the presence of both Zn(II) and Cu(II) shows that the cross-linking of Aβ through binding of Zn(II) to the Nτ atom of histidine is prevented by chelation of Cu(II) by the Nπ atom of histidine and nearby amide nitrogens. The inhibitory effect is strongest at a Cu/Aβ molar ratio of around 4. Above this ratio, Cu(II) itself promotes the Aβ aggregation by binding to the phenolate oxygen of Tyr10. These results emphasize the importance of regulation of Cu(II) levels to inhibit Aβ aggregation, and are consistent with an altered metal homeostasis in Alzheimer's disease.