Aggregation of amyloid beta -peptide (A beta), 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 A beta from the Zn(II)-induced aggregation. We demonstrate for the first time that Cu(II) effectively inhibits the A beta aggregation by competing with Zn(II) for histidine residues. The Raman spectrum of a metal-A beta complex in the presence of both Zn(II) and Cu(II) shows that the cross-linking of A beta through binding of Zn(II) to the N-tau atom of histidine is prevented by chelation. of Cu(II) by the N-pi atom of histidine and nearby amide nitrogens. The inhibitory effect is strongest at a Cu/A beta molar ratio of around 4. Above this ratio, Cu(II) itself promotes the A beta aggregation by binding to the phenolate oxygen of Tyr10. These results emphasize the importance of regulation of Cu(II) levels to inhibit A beta aggregation, and are consistent with an altered metal homeostasis in Alzheimer's disease.