Redox Reactions of Copper Complexes Formed with Different β-Amyloid Peptides and Their 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.

Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-β copper complex follow a preorganization mechanism

“…Results and Discussion Divergent reports of the electrochemistry of Aβ copper complexes have recently appeared (18)(19)(20). In the present study, we noticed that the cyclic voltamogramm of 0.2 mM Cu(Aβ) complex is strongly dependent of the peptide over copper ratio (Fig.…”

Modeling Cu2+-Aβ complexes from computational approaches

“…37,40 These latter species are expected to be particularly stable when both, His13 and His14, coordinate to the metal through the δ nitrogen of imidazole. 65 Computed SRP value for Ia is in very good agreement with the most recent experimental values determined for Cu 2+ -Aβ (1−16) complex (between 0.28 and 0.34V), 45,66,67 in accordance with the fact that this is the dominant species at pH ∼7.…”

“…40,41 It is worth mentioning that many experiments have also been done using the truncated Aβ (1-16) peptide, since it is more soluble than Aβ(1-42) and experimental evidences have shown that it can be very useful to understand its redox behavior, metal cation affinities, metal coordination and other physicochemical properties. 20,22,[42][43][44][45] Other truncated models such as Cu 2+ -Aβ(1-7) have been considered to study the mechanism of Cu 2+ reduction using quantum chemical methods, 37 but the interaction of Cu 2+ with larger systems including the whole Aβ(1-42) peptide have only been considered by means of classical molecular dynamic simulations. 46 The consideration of the full peptide Aβ(1-42) at the quantum mechanics level is computationally too expensive and thus, metal ion complexes are studied by using computational approaches that combine a quantum mechanical treatment for the copper coordination center and a molecular mechanics (MM) approach for the peptide moiety.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Toxicity of Aβ oligomers can be attenuated in cultures by copper chelation [176,177]. The mechanism of copper-Aβ induced cytotoxicity might involve oxidative stress, as the complex catalytically generates hydrogen peroxide [178][179][180]. The binding of copper to Aβ is likely to be a factor in AD because copper, too, is enriched in amyloid plaque [82].…”