Different Mechanisms of Oxidative Stress and Neurotoxicity for Alzheimer‘s Aβ(1−42) and Aβ(25−35)

Publisher Website
Google Scholar
Abstract
Oxidative stress induced by amyloid β-peptide (Aβ) has been implicated in the neurodegeneration observed in Alzheimer's disease (AD) brain. However, the mechanism by which the predominant form of Aβ found in AD brains, Aβ(1−42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, Aβ(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 Aβ(1−42) led us to investigate the cause for this enhanced toxicity of Aβ(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 Aβ(25−35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of Aβ(1−42) (valine) is appended to Aβ(25−35), the resultant peptide, Aβ(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 Aβ(25−35) and Aβ(1−42). The putative mechanistic role of methionine in the observed properties of Aβ peptides is discussed in the context of the obtained results as is the role of Aβ(1−42)-induced oxidative stress in the neurodegeneration found in AD brain.