Oxidative stress induced by amyloid beta -peptide (A beta) has been implicated in the neurodegeneration observed in Alzheimer's disease (AD) brain. However, the mechanism by which the predominant form of A beta found in AD brains, A beta (1-42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, A beta (25-35), as a convenient alternative in AD investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide. Our observation that the truncated peptide is more rapidly toxic and causes more oxidative damage than the parent A beta (1-42) led us to investigate the cause for this enhanced toxicity of A beta (25-35) in order to gain insight into the mechanism of action of these peptides. These studies reveal that two different mechanisms may be operative in the two peptides; however, the single methionine residue in the peptides appears to play a crucial role in both mechanisms. That methionine is C-terminal in qs(25-35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of A beta (1-42) (valine) is appended to A beta (25-35), the resultant peptide, A beta (25-36), in which methionine is no longer C-terminal, is neither toxic to cultured neurons nor does it cause oxidative damage. Additionally, oxidizing the sulfur of methionine to a sulfoxide abrogates the damaging effects of both A beta (25-35) and A beta (1-42). The putative mechanistic role of methionine in the observed properties of A beta peptides is discussed in the context of the obtained results as is the role of A beta (1-42)-induced oxidative stress in the neurodegeneration found in AD brain.