Methionine oxidation reduces lag-times for amyloid-β(1–40) fiber formation but generates highly fragmented fibers

• Methionine oxidation (MetOX) reduces the total amount of Aβ fibers generated.
• MetOX reduces lag-times for Aβ(1–40) fiber formation but extends lag-times for Aβ(1–42).
• MetOX perturbs amyloid structure and causes a marked reduction in Aβ fiber length.
• Preformed Aβ amyloid fibers are largely unaffected by hydrogen peroxide.
• MetOX promotes highly fragmented fiber assemblies of Aβ

Oxidative stress and the formation of amyloid plaques containing amyloid-β (Aβ) peptides are two key hallmarks of Alzheimer's disease. A proportion of methionine (Met) at position 35 within Aβ is oxidized to methionine sulphoxide (MetOX) within the Alzheimer's plaques. These oxidative processes may be the key to understanding the early stages of Alzheimer's disease. In vitro oxidation of Aβ, by the physiological oxidant H2O2, was monitored using 1H NMR and mass spectrometry. Here we investigate the effect of Aβ methionine oxidation on fiber formation kinetics and morphology using the amyloid specific fluorescence dye Thioflavin T (ThT) and Transmission Electron Microscopy (TEM). Methionine oxidation reduces the total amount of fibers generated for both dominant forms of Aβ, however there are marked differences in the effect of MetOX between Aβ(1–40) and Aβ(1–42). Surprisingly the presence of MetOX reduces lag-times for Aβ(1–40) fiber formation but extends lag-times for Aβ(1–42). TEM indicates a change in fiber morphology with a pronounced reduction in fiber length for both methionine oxidized Aβ(1–40) and Aβ(1–42). In contrast, the morphology of preformed amyloid fibers is largely unaffected by the presence of H2O2. Our studies suggest that methionine oxidation promotes highly fragmented fiber assemblies of Aβ. Oxidative stress associated with Alzheimer's disease can cause oxidation of methionine within Aβ and this in turn will influence the complex assembly of Aβ monomer into amyloid fibers, which is likely to impact Aβ toxicity.

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