Metal binding modes of Alzheimer's amyloid β-peptide in insoluble aggregates and soluble complexes

Aggregation of the amyloid beta-peptide (A beta) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) induces the A beta aggregation at acidic-to-neutral pH, while Cu(TI) is an effective inducer only at mildly acidic pH. We have examined Zn(II) and Cu(II) binding modes of A beta and their pH dependence by Raman spectroscopy. The Raman spectra dearly demonstrate that three histidine residues in the N-terminal hydrophilic region provide primary metal binding sites and the solubility of the metal-A beta complex is correlated with the metal binding mode. Zn(TI) binds to the N-tau atom of the histidine imidazole ring and the peptide aggregates through intermolecular His(N-tau)-Zn(II)-His(N-tau) bridges. The N-tau-metal ligation also occurs in Cu(II)-induced A beta aggregation at mildly acidic pH. At neutral pH, however, Cu(II) binds to N-pi, the other nitrogen of the histidine imidazole ring, and to deprotonated amide nitrogens of the peptide main chain. The chelation of Cu(II) by histidine and main-chain amide groups results in soluble Cu(II)-A beta complexes. Under normal physiological conditions, Cu(II) is expected to protect A beta against Zn(II)-induced aggregation by competing with Zn(TI) for histidine residues of A beta.