The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction

Biochemistry. 1999 Jun 15;38(24):7609-16. doi: 10.1021/bi990438f.

Abstract

Oxidative stress markers characterize the neuropathology both of Alzheimer's disease and of amyloid-bearing transgenic mice. The neurotoxicity of amyloid A beta peptides has been linked to peroxide generation in cell cultures by an unknown mechanism. We now show that human A beta directly produces hydrogen peroxide (H2O2) by a mechanism that involves the reduction of metal ions, Fe(III) or Cu(II), setting up conditions for Fenton-type chemistry. Spectrophotometric experiments establish that the A beta peptide reduces Fe(III) and Cu(II) to Fe(II) and Cu(I), respectively. Spectrochemical techniques are used to show that molecular oxygen is then trapped by A beta and reduced to H2O2 in a reaction that is driven by substoichiometric amounts of Fe(II) or Cu(I). In the presence of Cu(II) or Fe(III), A beta produces a positive thiobarbituric-reactive substance (TBARS) assay, compatible with the generation of the hydroxyl radical (OH.). The amounts of both reduced metal and TBARS reactivity are greatest when generated by A beta 1-42 >> A beta 1-40 > rat A beta 1-40, a chemical relationship that correlates with the participation of the native peptides in amyloid pathology. These findings indicate that the accumulation of A beta could be a direct source of oxidative stress in Alzheimer's disease.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Copper / chemistry
  • Copper / metabolism
  • Ferric Compounds / chemistry
  • Ferric Compounds / metabolism
  • Ferrous Compounds / chemistry
  • Ferrous Compounds / metabolism
  • Humans
  • Hydrogen Peroxide / chemistry
  • Hydrogen Peroxide / metabolism*
  • Macromolecular Substances
  • Metals, Heavy / chemistry
  • Metals, Heavy / metabolism*
  • Oxidation-Reduction
  • Rats
  • Species Specificity
  • Superoxides / chemistry
  • Superoxides / metabolism
  • Thiobarbituric Acid Reactive Substances / chemistry

Substances

  • Amyloid beta-Peptides
  • Ferric Compounds
  • Ferrous Compounds
  • Macromolecular Substances
  • Metals, Heavy
  • Thiobarbituric Acid Reactive Substances
  • Superoxides
  • Copper
  • Hydrogen Peroxide