Redox cycling of iron by Aβ42

3The amyloid cascade hypothesis and oxidative damage have been inextricably linked in the neurodegeneration that is characteristic of Alzheimer's disease. We have investigated this link and sought to suggest a mechanism whereby the precipitation of A beta(42) might contribute to the redox cycling of iron and hence the generation of reactive oxygen species via Fenton-like chemistry. We have shown that the critical step in the auto-oxidation of Fe(II) Under the near-physiological conditions of our study involved the generation of H2O2 via O-2(center dot-) and that A beta(42) influenced Fenton chemistry through aggregation state-specific binding of both Fe(II) and Fe(III). The net result of these interactions was the delayed precipitation of kinetically redox-mactive Fe(OH)(3(s)) Such that Fe(II)/Fe(III) were cycled in redox-active forms over a substantially longertime period than if peptide had been absent from preparations. The addition of physiologically significant concentrations of either Cu(II) or Zn(II) reduced the role played by A beta(42) in the Fe(II)/Fe(III) redox cycle whereas a pathophysiologically significant concentration of AI(III) potentiated the redox cycle in favour of Fe(II) whether or not Cu(II) or Zn(II) was additionally present. The results support the notion that oxidative damage in the immediate vicinity of, for example, senile plaques, may be the result of Fenton chemistry catalysed by the codeposition of ANI with metals such as Fe(II)/Fe(III) and Al(III). (c) 2005 Elsevier Inc. All rights reserved.