Oxidation of Methionine-35 Attenuates Formation of Amyloid β-Peptide 1-40 Oligomers

• Amyloid plaques formed by aggregation of the amyloid β-peptide (Aβ) are an intrinsic component of Alzheimer disease pathogenesis. It has been suggested that oxidation of methionine 35 in Aβ has implications for Alzheimer disease, and it has been shown that oxidation of Met-35 significantly inhibits aggregation in vitro. In this study, the aggregational properties of Aβ-(1–40) before and after Met-35 oxidation were investigated using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. The results show that Aβ-(1–40)Met-35(O) trimer and tetramer formation is significantly attenuated as compared with Aβ-(1–40). This suggests that oxidation of Met-35 inhibits a conformational switch in Aβ-(1–40) necessary for trimer but not dimer formation. Random incorporation of Aβ-(1–40) and Aβ-(1–40)Met-35(O) in homo- and heterooligomers could also be observed. This is the first report of an early rate-limiting step in Aβ-(1–40) aggregation. Slowing of the fibrillization process at this early step is likely to support prolonged solubility and clearance of Aβ from brain and may reduce disease progression.

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NATURVETENSKAP  -- Kemi -- Analytisk kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences -- Analytical Chemistry (hsv//eng)

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