Possible involvement of copper(II) in Alzheimer disease.

Abstract

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.

Liquid chromatography/tandem mass spectrometry characterization of oxidized amyloid beta peptides as potential biomarkers of Alzheimer's disease

“…Experimental evidence is mounting to suggest that simple aggregation of Ab may not be the only cause of plaque deposition. [35][36][37] Several studies have shown that oxidation of Ab occurs through the formation of Cu I and subsequent generation of ROS from molecular oxygen. [38][39][40] This process is thought to depend on the presence of three His residues that are present at the N-terminus, His 6 , His…”

“…Sites of oxidation were then unequivocally characterized as histidine-13 and histidine-14 by LC/tandem mass spectrometric (MS/ MS) analysis of the tryptic peptides. The ability to analyze the specific amyloid b 6-16 tryptic fragments derived from full-length amyloid b peptides will make it possible to determine whether oxidation in vivo occurs at specific histidine residues and/or at other amino acid residues such as methionine- 35 Studies of subjects with early onset of Alzheimer's disease (AD) have indicated that metabolism and/or modification of amyloid-beta (Ab) peptides is involved. 1 The Ab cascade hypothesis suggests that excessive plaque formation results from deposition of Ab peptides in the brain and that is an important step in the pathogenesis of AD.…”

“…[41][42][43][44][45] It has been suggested that Cu ions together with ROS are involved in the oxidation of Ab and that this may play an important role in AD. [7][8][9] There is also substantial evidence accruing to suggest that Met 35 may play a role in plaque formation. 46 For example, replacement of sulfur in Met 35 by a methylene group (norleucine) attenuated the oxidative stress and neurotoxicity that was induced by Ab .…”

Gene expression profiling in chronic copper overload reveals upregulation ofPrnpandApp

“…The homeostasis of copper is significantly altered in the AD brain (57). Copper inhibits ␤-amyloid production by stimulating the non-amyloidogenic pathway of APP (5); however, in vitro, copper induces aggregation of the soluble amyloid peptide, suggesting a role in both the processing of APP and amyloid plaque assembly and may contribute to AD development (24). App Ϫ/Ϫ mice have increased copper in their livers and in the cerebral cortex, with no change in their serum (63).…”

Comparison of Two Methods for the Estimation of Stability of Copper(II) Bis-Complexes with Aromatic Ligands Relevant to Alzheimer’s Disease

“…Alzheimer's disease (AD), the leading mental disorder of the elderly population in developed countries, is closely related to copper metabolism (1). Next to the liver, the brain contains the second highest cellular concentration of copper, which is more frequent in grey matter (60 μmol L -1 to 110 μmol L -1 ) than in white matter (25 μmol L -1 to 79 μmol L -1 ) (2).…”