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

Amyloid beta-peptide (A beta), 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 A beta(1-40), found in AD brain, and the amyloid fragment A beta(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 A beta(1-40) and A beta(25-35), and the substitution of methionine by valine; or the removal of the methionine in A beta(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 A beta-associated free radical oxidative stress that involves methionine, and to the use of spin trapping methods to infer mechanistic information about A beta. (C) 1999 Elsevier Science Inc.