Metal Binding Modes of Alzheimer's Amyloid β-Peptide in Insoluble Aggregates and Soluble Complexes

Abstract

Aggregation of the amyloid beta-peptide (Abeta) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) induces the Abeta aggregation at acidic-to-neutral pH, while Cu(II) is an effective inducer only at mildly acidic pH. We have examined Zn(II) and Cu(II) binding modes of Abeta and their pH dependence by Raman spectroscopy. The Raman spectra clearly demonstrate that three histidine residues in the N-terminal hydrophilic region provide primary metal binding sites and the solubility of the metal-Abeta complex is correlated with the metal binding mode. Zn(II) 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 Abeta 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)-Abeta complexes. Under normal physiological conditions, Cu(II) is expected to protect Abeta against Zn(II)-induced aggregation by competing with Zn(II) for histidine residues of Abeta.

Long Distance Charge Redistribution Upon Cu,Zn-Superoxide Dismutase Reduction

“…Comparison of the IR spectra of MeIm with those of MeIm in solutions containing Cu 2ϩ or Zn 2ϩ at MeIm/metal ratios of 4 ( Fig. 3, B-D) showed that the formation of Cu-4(5)MeImH and Zn-4(5)MeImH complexes induced an upshift of the (C 4 C 5 ) mode of methylimidazole, in total agreement with that reported with Raman spectroscopy (28,(77)(78)(79). Thus, the IR bands at 1605 cm Ϫ1 in Fig.…”

“…This was precisely described on His-Cu and His-Zn models of known structure, as well as on peptides modeling the copper-binding site of the prion protein, or the zinc/ copper-binding site of amyloid ␤-peptides (28,(77)(78)(79). The (C 4 C 5 ) mode occurs at 1590 -1580 cm Ϫ1 for histidine coordinated with N to copper or zinc (Scheme 2d) and at higher frequency, 1606 -1594 cm Ϫ1 , for histidine coordinated with N (28, 77-79) (Scheme 2 and Table I).…”

Modulating Amyloid Self-Assembly and Fibril Morphology with Zn(II)

“…We now extend the use of metal ions as probes of amyloid side chain packing in simple segments of the Aβ peptide of Alzheimer's disease. By restricting the possible metal binding sites, we show that Zn 2+ can specifically control the rate of self-assembly and dramatically regulate amyloid morphology via distinct coordination environments.The histidine dyad, His13 and His14, of Aβ is implicated in metal binding 8,9 and the metalmediated toxicity of Aβ. [10][11][12][13] In a parallel, in-register β-sheet arrangement with sheet Hbonds oriented along the fibril axis (Figure 1a.), 3,4 the side chains of the His13 and His14 are spaced 5 Å apart along each surface of the β-sheets (Figure 1b).…”

Copper brain homeostasis: Role of amyloid precursor protein and prion protein

“…The interaction between copper and Ab induces its aggregation in vitro (11) and favours Ab amyloid deposition in vivo, co-localizing in senile plaques; in fact, copper, iron and zinc levels increase in plaques up to 0.4 mM copper and up to 1 mM iron and zinc (12). Treatment with a copper-zinc chelator markedly and rapidly inhibits amyloid deposition in the brain of Alzheimer's disease transgenic mice (13).…”