title: Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils.
abstract: The amyloid-beta(1-42) (Abeta42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the beta-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Abeta42 oligomers to fibrils involves the association of these loosely aggregated strands into beta-sheets whose individual beta-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
authors.forename: Mahiuddin
authors.initials: M
authors.lastname: Ahmed
authors.forename: Judianne
authors.initials: J
authors.lastname: Davis
authors.forename: Darryl
authors.initials: D
authors.lastname: Aucoin
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.forename: Shivani
authors.initials: S
authors.lastname: Ahuja
authors.forename: Saburo
authors.initials: S
authors.lastname: Aimoto
authors.forename: James I
authors.initials: JI
authors.lastname: Elliott
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003080:Cold Temperature; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D012492:Salts / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012492:Salts; C075222:amyloid beta-protein (1-42)
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