Affiliations: [a] Department of Chemistry, Center for Membrane Sciences, University of Kentucky Lexington, KY 40506-0055, USA | [b] Sanders-Brown Center on Aging, University of Kentucky Lexington, KY 40506-0055, USA
Correspondence:
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Corresponding author: Professor D. Allan Butterfield, Department of Chemistry, Center for Membrane Sciences, and Sanders-Brown Center on Aging, 121 Chemistry-Physics Building, University of Kentucky, Lexington, KY 40506-0055, USA. Tel.: +1 859 257 3184; Fax: +1 859 257 5876; E-mail: dabcns@uky.edu.
Abstract: Alzheimer's disease is a neurodegenerative disorder associated with aging and cognitive decline. Amyloid beta peptide (1–42) [Aβ(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 β(1–42) may play a critical role in Aβ(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 Aβ is less likely to form larger β-sheet structures, and consequently, large aggregates. As a consequence of the lack of deposition of the peptide in rodent brain, rodent Aβ has been proposed to be non-toxic. Additionally, the sequence of the rodent variety of Aβ(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 Aβ peptide to reduce Cu(II) to Cu(I) compared to the human Aβ 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 β has been proposed to lack oxidative stress properties. In this study, the oxidative stress and neurotoxic properties of rodent β(1–42) [Aβ(1–42)Rat] were evaluated and compared to those of human Aβ(1–42). Both human Aβ(1–42) and β(1–42)Rat were found to have a significant effect on neuronal DNA fragmentation, loss of neuritic networks, and cell viability. β(1–42) Rat was found to cause a significant increase in both protein oxidation and lipid peroxidation, similar to Aβ(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 Aβ-mediated toxicity. Taken together, these results suggest that Cu(II) reduction may not play a critical role inβ(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 β(1–42) peptide.
