title: Different mechanisms of oxidative stress and neurotoxicity for Alzheimer's A beta(1--42) and A beta(25--35).
abstract: 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 A beta(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.
authors.affiliation: Departments of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055, USA.
authors.forename: S
authors.initials: S
authors.lastname: Varadarajan
authors.forename: J
authors.initials: J
authors.lastname: Kanski
authors.forename: M
authors.initials: M
authors.lastname: Aksenova
authors.forename: C
authors.initials: C
authors.lastname: Lauderback
authors.forename: D A
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008715:Methionine / Q000378:metabolism / Q000494:pharmacology; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011506:Proteins; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C439320:amyloid beta-protein (25-36); D008715:Methionine