title: Rodent Abeta(1-42) exhibits oxidative stress properties similar to those of human Abeta(1-42): Implications for proposed mechanisms of toxicity.
abstract: Alzheimer's disease is a neurodegenerative disorder associated with aging and cognitive decline. Amyloid beta peptide (1-42) [Abeta(1-42)] is a primary constituent of senile plaques - a hallmark of Alzheimer's disease - and has been implicated in the pathogenesis of the disease. Previous studies have shown that methionine residue 35 of beta(1-42) may play a critical role in Abeta(1-42)-mediated oxidative stress and neurotoxicity. Several additional mechanisms of neurotoxicity have been proposed, including the role of Cu(II) binding and reduction to produce hydrogen peroxide and the role of peptide aggregation. It has been reported that rodent Abeta is less likely to form larger beta-sheet structures, and consequently, large aggregates. As a consequence of the lack of deposition of the peptide in rodent brain, rodent Abeta has been proposed to be non-toxic. Additionally, the sequence of the rodent variety of Abeta(1-42) contains three amino acid substitutions compared to the human sequence. These substitutions include the shift of arginine 5, trysosine 10, and histidine 13 to glycine, phenylalanine, and arginine, respectively. This shift in sequence within the Cu(II) binding region of the peptide results in a decrease in the ability of the rodent Abeta peptide to reduce Cu(II) to Cu(I) compared to the human Abeta peptide. As a result of the effect of the amino acid variations on the ability of the rodent peptide to reduce Cu(II) to Cu(I) compared to the human peptide, the rodent beta has been proposed to lack oxidative stress properties. In this study, the oxidative stress and neurotoxic properties of rodent beta(1-42) [Abeta(1-42)Rat] were evaluated and compared to those of human Abeta(1-42). Both human Abeta(1-42) and beta(1-42)Rat were found to have a significant effect on neuronal DNA fragmentation, loss of neuritic networks, and cell viability. beta(1-42) Rat was found to cause a significant increase in both protein oxidation and lipid peroxidation, similar to Abeta(1-42), both of which were inhibited by the lipid-soluble, chain breaking antioxidant vitamin E, suggesting that reactive oxygen species play a role in the Abeta-mediated toxicity. Taken together, these results suggest that Cu(II) reduction may not play a critical role inbeta(1-42)Rat-induced oxidative stress, and that the oxidative stress exhibited by this peptide may be a consequence of the presence of methionine 35, similar to the findings associated with the native human beta(1-42) peptide.
authors.affiliation: Department of Chemistry, Center for Membrane Sciences, University of Kentucky Lexington, KY 40506-0055, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Boyd-Kimball
authors.forename: Rukhsana
authors.initials: R
authors.lastname: Sultana
authors.forename: Hafiz
authors.initials: H
authors.lastname: Mohmmad-Abdul
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008715:Methionine / Q000737:chemistry; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
chemical_list: D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D008051:Lipid Bilayers; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D008715:Methionine