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The beta-amyloid (Abeta) peptide is a principal component of insoluble amyloid plaques that are characteristic neuropathological features of Alzheimer disease (AD). The amyloid peptide also exists as a normal soluble protein that undergoes a pathogenic transition to an aggregated, fibrous form. This transition can be affected by extraneous proteinaceous elements and nonproteinaceous elements such as copper ions, which may promote aggregation and/or stabilization of the fibrils. Copper has been found in abnormally high concentrations in amyloid plaques and AD-affected neuropil, and copper-selective chelators have been shown to dissolve Abeta peptide from postmortem brain specimens. Although Cu(2+) is an essential element for life and the function of numerous enzymes is basic to neurobiology, free or incorrectly bound Cu(2+) can also catalyze generation of the most damaging radicals, such as hydroxyl radical, giving a chemical modification of the protein, alternations in protein structure and solubility, and oxidative damage to surrounding tissue.

A potentiometric and spectroscopic (UV-Vis, CD, NMR and EPR) study of copper() bonding to the N-terminal (11-16) of human and mouse fragments of β-amyloid peptide (EVHHQK-NH 2 , EVRHQK-NH 2 and their Nblocked derivatives) was performed. The results indicate that the hexapeptide amide EVHHQK-NH 2 forms in the pH range 4.5-10.5 complexes in which the coordination of copper() is typical {NH 2 , 2N Ϫ , N Im } for the peptide sequence Xaa-Yaa-His. The mouse fragment containing the N-terminal amino group free in a wide pH range is coordinated through the terminal amino group, carbonyl oxygen or one or two deprotonated amide nitrogens from the N-termini, while the fourth coordination site is occupied by a nitrogen donor of imidazole in the form of a macrochelate. When the amino group is blocked (Ac-EVRHQK-NH 2 ) the imidazole nitrogen of the histidine residue acts as an anchoring bonding site and at higher pH the 3N and 4N complexes are formed with the amide nitrogens coordinated. A blocked hexapeptide modeling a part of human β-amyloid peptide (Ac-EVHHQK-NH 2 ) forms complexes with coordination through imidazole nitrogens both of histidine residues over a broad pH range. With increasing pH the amide nitrogens are also coordinated. In a wide pH range including physiological, Ac-EVHHQK-NH 2 (human fragment) is much more effective in copper() ion bonding than is Ac-EVRHQK-NH 2 (mouse fragment).

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