Soluble Amyloid β₁₋₂₈−Copper(I)/Copper(II)/Iron(II) Complexes Are Potent Antioxidants in Cell-Free Systems

Abstract

Amyloid beta (Abeta) is a central characteristic of Alzheimer's disease (AD). Currently, there is a long-standing dispute regarding the role of Abeta-metal ion (Zn, Cu, and Fe) complexes in AD pathogenesis. Here, we aim to decipher the connection between oxidative damage implicated in AD and Abeta-metal ion complexes. For this purpose we study, using ESR, the modulation of Cu/Fe-induced H 2O 2 decomposition by Abeta 1-28 (Abeta 28), a soluble model of Abeta 40/42. The addition of H 2O 2 to 0.6 nM-360 microM Abeta 28 solutions containing 100 microM Cu(II)/Cu(I)/Fe(II) at pH 6.6 results in a concentration-dependent sigmoidal decay of [*OH] with IC 50 values of 61, 59, and 84 microM, respectively. Furthermore, Abeta 28 reduces 90% of *OH production rate in the Cu(I)-H 2O 2 system in 5 min. Unlike soluble Abeta 28, Abeta 28-Cu aggregates exhibit poor antioxidant activity. The mode of antioxidant activity of soluble Abeta 28 is twofold. The primary (rapid) mechanism involves metal chelation, whereas the secondary (slow) mechanism involves (*)OH scavenging and oxidation of Cu(Fe)-coordinating ligands. On the basis of our findings, we propose that soluble Abeta may play a protective role in the early stages of AD, but not in healthy individuals, where Abeta's concentration is nanomolar. Yet, when Abeta-metal ion complexes undergo aggregation, they significantly lose their protective function and allow oxidative damage to occur.

Asiaticoside ameliorates β-amyloid-induced learning and memory deficits in rats by inhibiting mitochondrial apoptosis and reducing inflammatory factors

“…Furthermore, intracerebroventricular injection of low doses of Aβ 25–35 (31) or Aβ 1–28 (32,33) has also been shown to influence the spatial memory function and Y-maze alternation behavior in mice. MWM spatial learning test is typically used in the evaluation of rodent models for cognitive disorders and possible treatments (34,35).…”

Ternary Complexes of Iron, Amyloid-β, and Nitrilotriacetic Acid: Binding Affinities, Redox Properties, and Relevance to Iron-Induced Oxidative Stress in Alzheimer’s Disease

“…A recent study by Fischer and coworker showed that the Fe(II)-catalyzed generation of free radicals from H 2 O 2 is halted by addition of Aβ. (16) By measuring dissociation constants of the complexes formed between Aβ and Fe(III)-NTA or Fe(II)-NTA, insight can be gained into the role of Aβ in iron sequestration and the possible oxidative stress induced by iron. We note that the measured binding affinity (K d = 6.3 × 10 -21 ) is close to those of transferrin (2.5 × 10 -21 and 4.0 ×10 -20 for the first and second iron respectively)(33).…”

“…(13-16) It is shown that the hydrophilic domain (residues 1-16) of the full-length Aβ can ligate Cu(II) through its histidine and possibly glutamate, aspartate and/or tyrosine residues. (4, 14, 17, 18) A Raman analysis of postmortem brain samples has also confirmed the existence of the Aβ-Cu complex in senile plaques.…”

Structural Studies of Copper(I) Complexes of Amyloid‐β Peptide Fragments: Formation of Two‐Coordinate Bis(histidine) Complexes

“…However, few direct studies of Cu I binding or reactivity with Ab peptides or fragments have been reported. [5,6] We have studied the interactions of the hydrophilic Nterminal region of the Ab peptide with Cu…”