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Redox reactions of copper complexes formed with different beta-amyloid peptides and their neuropathological [correction of neuropathalogical] relevance.

ABSTRACT: The binding stoichiometry between Cu(II) and the full-length beta-amyloid Abeta(1-42) and the oxidation state of copper in the resultant complex were determined by electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry. The same approach was extended to the copper complexes of Abeta(1-16) and Abeta(1-28). A stoichiometric ratio of 1:1 was directly observed, and the oxidation state of copper was deduced to be 2+ for all of the complexes, and residues tyrosine-10 and methionine-35 are not oxidized in the Abeta(1-42)-Cu(II) complex. The stoichiometric ratio remains the same in the presence of more than a 10-fold excess of Cu(II). Redox potentials of the sole tyrosine residue and the Cu(II) center were determined to be ca. 0.75 and 0.08 V vs Ag/AgCl [or 0.95 and 0.28 V vs normal hydrogen electrode (NHE)], respectively. More importantly, for the first time, the Abeta-Cu(I) complex has been generated electrochemically and was found to catalyze the reduction of oxygen to produce hydrogen peroxide. The voltammetric behaviors of the three Abeta segments suggest that diffusion of oxygen to the metal center can be affected by the length and hydrophobicity of the Abeta peptide. The determination and assignment of the redox potentials clarify some misconceptions in the redox reactions involving Abeta and provide new insight into the possible roles of redox metal ions in the Alzheimer's disease (AD) pathogenesis. In cellular environments, the reduction potential of the Abeta-Cu(II) complex is sufficiently high to react with antioxidants (e.g., ascorbic acid) and cellular redox buffers (e.g., glutathione), and the Abeta-Cu(I) complex produced could subsequently reduce oxygen to form hydrogen peroxide via a catalytic cycle. Using voltammetry, the Abeta-Cu(II) complex formed in solution was found to be readily reduced by ascorbic acid. Hydrogen peroxide produced, in addition to its role in damaging DNA, protein, and lipid molecules, can also be involved in the further consumption of antioxidants, causing their depletion in neurons and eventually damaging the neuronal defense system. Another possibility is that Abeta-Cu(II) could react with species involved in the cascade of electron transfer events of mitochondria and might potentially sidetrack the electron transfer processes in the respiratory chain, leading to mitochondrial dysfunction.

SUBMITTER: Jiang D

PROVIDER: S-EPMC3222686 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Redox reactions of copper complexes formed with different beta-amyloid peptides and their neuropathological [correction of neuropathalogical] relevance.

Jiang Dianlu D Men Lijie L Wang Jianxiu J Zhang Yi Y Chickenyen Sara S Wang Yinsheng Y Zhou Feimeng F

Biochemistry 20070718 32

The binding stoichiometry between Cu(II) and the full-length beta-amyloid Abeta(1-42) and the oxidation state of copper in the resultant complex were determined by electrospray ionization-Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS) and cyclic voltammetry. The same approach was extended to the copper complexes of Abeta(1-16) and Abeta(1-28). A stoichiometric ratio of 1:1 was directly observed, and the oxidation state of copper was deduced to be 2+ for all of the com ...[more]

PMID: 17636872

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Project description:The interaction of amyloid-beta (Abeta) and redox-active metals, two important biomarkers present in the senile plaques of Alzheimer's disease (AD) brain, has been suggested to enhance the Abeta aggregation or facilitate the generation of reactive oxygen species (ROS). This study investigates the nature of the interaction between the metal-binding domain of Abeta, viz., Abeta(1-16), and the Fe(III) or Fe(II) complex with nitrilotriacetic acid (NTA). Using electrospray ionization mass spectrometry (ESI-MS), the formation of a ternary complex of Abeta(1-16), Fe(III), and NTA with a stoichiometry of 1:1:1 was identified. MS also revealed that the NTA moiety can be detached via collision-induced dissociation. The cumulative dissociation constants of both Abeta-Fe(III)-NTA and Abeta-Fe(II)-NTA complexes were deduced to be 6.3 x 10(-21) and 5.0 x 10(-12) M(2), respectively, via measurement of the fluorescence quenching of the sole tyrosine residue on Abeta upon formation of the complex. The redox properties of these two complexes were investigated by cyclic voltammetry. The redox potential of the Abeta-Fe(III)-NTA complex was found to be 0.03 V versus Ag/AgCl, which is negatively shifted by 0.54 V when compared to the redox potential of free Fe(III)/Fe(II). Despite such a large potential modulation, the redox potential of the Abeta-Fe(III)-NTA complex is still sufficiently high for a range of redox reactions with cellular species to occur. The Abeta-Fe(II)-NTA complex electrogenerated from the Abeta-Fe(III)-NTA complex was also found to catalyze the reduction of oxygen to produce H(2)O(2). These findings provide significant insight into the role of iron and Abeta in the development of AD. The binding of iron by Abeta modulates the redox potential to a level at which its redox cycling occurs. In the presence of a biological reductant (antioxidant), redox cycling of iron could disrupt the redox balance within the cellular milieu. As a consequence, not only is ROS continuously produced, but oxygen and biological reductants can also be depleted. A cascade of biological processes can therefore be affected. In addition, the strong binding affinity of Abeta toward Fe(III) and Fe(II) indicates Abeta could compete for iron against other iron-containing proteins. In particular, its strong affinity for Fe(II), which is 8 orders of magnitude stronger than that of transferrin, would greatly interfere with iron homeostasis.

Dataset Information

Redox reactions of copper complexes formed with different beta-amyloid peptides and their neuropathological [correction of neuropathalogical] relevance.

Publications

Redox reactions of copper complexes formed with different beta-amyloid peptides and their neuropathological [correction of neuropathalogical] relevance.

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