Different mechanisms of oxidative stress and neurotoxicity for Alzheimer'sA beta(1-42) and A beta(25-35)

Oxidative stress induced by amyloid beta -peptide (A beta) has been implica ted in the neurodegeneration observed in Alzheimer's disease (AD) brain. Ho wever, the mechanism by which the predominant form of A beta found in AD br ains, A beta (1-42), causes oxidative stress and neurotoxicity remains unkn own. 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 toxicologica l and oxidative stress properties of the native full-length peptide. Our ob servation 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 ca use for this enhanced toxicity of A beta (25-35) in order to gain insight i nto the mechanism of action of these peptides. These studies reveal that tw o different mechanisms may be operative in the two peptides; however, the s ingle 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 sequenc e of A beta (1-42) (valine) is appended to A beta (25-35), the resultant pe ptide, A beta (25-36), in which methionine is no longer C-terminal, is neit her toxic to cultured neurons nor does it cause oxidative damage. Additiona lly, oxidizing the sulfur of methionine to a sulfoxide abrogates the damagi ng effects of both A beta (25-35) and A beta (1-42). The putative mechanist ic role of methionine in the observed properties of A beta peptides is disc ussed 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.