Possible involvement of copper(II) in Alzheimer disease.

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.

Coordination of copper(II) ions by the 11-20 and 11-28 fragments of human and mouse beta-amyloid peptide.

A potentiometric and spectroscopic (UV-vis, CD and EPR) study of Cu(II) binding to the (11-20), (11-28), (Ac-11-20H) and (Ac-11-28) fragments of human (H) and mouse (M) beta-amyloid peptide was carried out. The values of the protonation constants of the two lysine side chain amino groups for the (11-28) and (Ac-11-28) fragments of beta-amyloid peptide differ noticeably suggesting considerable interactions between the two residues. The N-terminal amino acid sequence Xaa-Yaa-His for the (11-20H) and (11-28H) fragments determines the coordination ability of the fragments studied to copper(II) ions. Addition of the (17-20) and (17-28) sequences to the (11-16) fragment of human and mouse beta-amyloid peptide does not change the coordination mode, and the stabilities of the complexes formed are comparable to those of the (11-16) peptide, although 1N complexes of the (11-28) fragments are stabilized by about one order of magnitude compared to those of the (11-16) peptides. The (Ac-11-28) peptides form complexes with the same coordination mode as those for the (Ac-11-16) fragments. The stability of the complexes for the (Ac-11-28H) fragment is one or two orders of magnitude higher compared to those of the (Ac-11-16H) fragment. This stabilization may result from structural organization of a peptide in copper(II) complexes.