The hydrophobic environment of Met35 of Alzheimer's Aβ(1-42) is important for the neurotoxic and oxidative properties of the peptide

In Alzheimer's disease (AD) brain increased lipid peroxidation is found. Amyloid β-peptide [Aβ(1-42)] induces oxidative stress (including lipid peroxidation) and neurotoxicity, and the single methionine residue (Met35) is important for these properties. In the current study, we tested the hypothesis that removal of Met35 from lipid bilayer would abrogate the oxidative stress and neurotoxic properties of Aβ(1-42), i.e. we tested the hypothesis and found that lipid peroxidation initiated by oxidation of the Met35 is an early event in Aβ(1-42) neurotoxicity. Substitution of negatively charged aspartic acid for glycine residue 37 is not predicted to bring the Met35 residue out of the hydrophobic lipid bilayer. In this study, we showed that G37D substitution in Aβ(1-42) completely abolishes neurotoxic and oxidative processes associated with the parent peptide. This is demonstrated by the lack of cell toxicity and protein oxidation in contrast to the treatment with native Aβ(1-42). Additionally, the G37D peptide does not display the aggregation properties that are associated with native Aβ as seen in the thioflavin T (ThT) assay and fibril morphology. The results presented in this work are thus consistent with the notion of the importance of methionine 35 of Aβ(1-42) in the lipid-initiated oxidative cascade and subsequent neurotoxicity in AD brain.