title: Oxidation of methionine 35 attenuates formation of amyloid beta -peptide 1-40 oligomers.
abstract: Amyloid plaques formed by aggregation of the amyloid beta-peptide (Abeta) are an intrinsic component of Alzheimer disease pathogenesis. It has been suggested that oxidation of methionine 35 in Abeta 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 Abeta-(1-40) before and after Met-35 oxidation were investigated using electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. The results show that Abeta-(1-40)Met-35(O) trimer and tetramer formation is significantly attenuated as compared with Abeta-(1-40). This suggests that oxidation of Met-35 inhibits a conformational switch in Abeta-(1-40) necessary for trimer but not dimer formation. Random incorporation of Abeta-(1-40) and Abeta-(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 Abeta-(1-40) aggregation. Slowing of the fibrillization process at this early step is likely to support prolonged solubility and clearance of Abeta from brain and may reduce disease progression.
authors.affiliation: Division of Ion Physics, The Angström Laboratory, Uppsala University, Box 534, SE-751 21 Uppsala, Sweden. magnus.palmblad@angstrom.uu.se
authors.forename: Magnus
authors.initials: M
authors.lastname: Palmblad
authors.forename: Anita
authors.initials: A
authors.lastname: Westlind-Danielsson
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D017357:Cyclotrons; D019281:Dimerization; D006801:Humans; D007700:Kinetics; D013058:Mass Spectrometry; D008715:Methionine / Q000737:chemistry* / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D014867:Water; D008715:Methionine; D010100:Oxygen