Methionine residue 35 is important in amyloid beta-peptide-associated freeradical 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 radi cal oxidative stress that may lead to neurodegeneration, In the current stu dy 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 product ion. The methionine residue in these peptides is believed to play an import ant role in their neurotoxicity. Substitution of methionine by structurally similar norleucine in both A beta(1-40) and A beta(25-35), and the substit ution of methionine by valine; or the removal of the methionine in A beta(2 5-35), abrogates free radical production and protein oxidation of and toxic ity to hippocampal neurons. These results are discussed with relevance to t he hypothesis that neurodegeneration in Alzheimer's disease may be due in p art to A beta-associated free radical oxidative stress that involves methio nine, and to the use of spin trapping methods to infer mechanistic informat ion about A beta. (C) 1999 Elsevier Science Inc.