Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress

Brain Res Bull. 1999 Sep 15;50(2):133-41. doi: 10.1016/s0361-9230(99)00093-3.

Abstract

Amyloid beta-peptide (Abeta), the central constituent of senile plaques in Alzheimer's disease (AD) brain, has been shown to be a source of free radical oxidative stress that may lead to neurodegeneration. In the current study Abeta(1-40), found in AD brain, and the amyloid fragment Abeta(25-35) were used in conjunction with electron paramagnetic resonance spin trapping techniques to demonstrate that these peptides mediate free radical production. The methionine residue in these peptides is believed to play an important role in their neurotoxicity. Substitution of methionine by structurally similar norleucine in both Abeta(1-40) and Abeta(25-35), and the substitution of methionine by valine, or the removal of the methionine in Abeta(25-35), abrogates free radical production and protein oxidation of and toxicity to hippocampal neurons. These results are discussed with relevance to the hypothesis that neurodegeneration in Alzheimer's disease may be due in part to Abeta-associated free radical oxidative stress that involves methionine, and to the use of spin trapping methods to infer mechanistic information about Abeta.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / physiopathology*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / physiology*
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Cells, Cultured
  • Fetus / cytology
  • Free Radicals / adverse effects
  • Free Radicals / pharmacology
  • Methionine / metabolism*
  • Methionine / toxicity*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurotoxins / pharmacology
  • Oxidative Stress / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Spin Trapping / methods
  • Tetrazolium Salts
  • Trypan Blue

Substances

  • Amyloid beta-Peptides
  • Free Radicals
  • Neurotoxins
  • Tetrazolium Salts
  • Methionine
  • Trypan Blue