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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.

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Stability constants and ligand donor sets of the copper(II) complexes of the NH2-29-56(L1)(AA30GKTKEGVLYV40GSKTKEGVVH50GVATVA56-NH2), NH2-M29-D30-56(L2) and Ac-M29-D30-56(L3) fragments of alpha-synuclein were determined in aqueous solution for 1 : 1 metal-to-ligand molar ratio in the pH range 2.5-10.5. The tyrosine residue in the 39th position of the alpha-synuclein fragments does not take part in the coordination of the metal ion. The potentiometric and spectroscopic data (UV-Vis, CD, EPR) show that acetylation of the amino terminal group induces significant changes in the coordination properties of the L3 fragment compared to that of the L2 peptide. When the amino group is blocked (L3) the imidazole nitrogen of the histidine residue acts as an anchoring site and at higher pH the 3N {N(Im),2N-} and 4N {N(Im),3N-} complexes are formed. The L1 peptide at physiological pH forms in equilibrium 3N {NH2,N-,CO,N(Im)} and 4N {NH2,2N-,N(Im)} complexes. For the L2 peptide the coordination of the copper(II) ions starts from the N-terminal Met residue and with increasing of pH the Asp residue in second position of amino acid sequence coordinates and stabilizes significantly the 2N complex as a result of chelation through the beta-carboxylate group. At physiological pH the 3N {NH2,N-,beta-COO-,N(Im)} coordination mode dominates. At pH above 6 the results for the L2 fragment suggest the formation of 3N and 4N complexes (in equatorial plane) and the involvement of the lateral NH2 group of Lys residue in the axial coordination of Cu(II) ion. In CD spectra sigma (epsilon-NH2-Lys) --> Cu(II) charge transfer transition is observed. The stability constants for the L2 fragment of alpha-synuclein of the 4N {NH2,2N-,N(Im)} and {NH2,3N-} complexes are higher about 1.5 and 0.7 orders of magnitude, respectively, by comparison to those of the L1 peptide. This increase may be explained by the involvement of the epsilon-NH2 group of Lys residue in the coordination sphere of metal ion.

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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