Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's Aβ(1-42) and Aβ(25-35)

S. Varadarajan, J. Kanski, M. Aksenova, C. Lauderback, D. A. Butterfield

Research output: Contribution to journalArticlepeer-review

318 Scopus citations


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, A(β25-36), 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.

Original languageEnglish
Pages (from-to)5625-5631
Number of pages7
JournalJournal of the American Chemical Society
Issue number24
StatePublished - 2001

ASJC Scopus subject areas

  • Catalysis
  • Chemistry (all)
  • Biochemistry
  • Colloid and Surface Chemistry


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