title: Direct evidence for self-propagation of different amyloid-β fibril conformations.
abstract: BACKGROUND
  Amyloid fibrils formed by amyloid-β (Aβ) peptides are associated with Alzheimer's disease and can occur in a range of distinct morphologies that are not uniquely determined by the Aβ sequence. Whether distinct conformations of Aβ fibrils can be stably propagated over multiple cycles of seeding and fibril growth has not been established experimentally.
  
  
  OBJECTIVE
  The ability of the 40-residue peptide Aβ1-40 to assemble into fibrils with the conformation of the mutant Aβ1-40 peptide containing the 'Osaka' mutation E22Δ was investigated.
  
  
  METHODS
  Fibril formation of highly pure, recombinant Aβ1-40 in the presence of distinct, preformed seeds in vitro was recorded with thioflavin T fluorescence, and distinct fibrillar structures were identified and distinguished by fluorescence spectroscopy and electron microscopy.
  
  
  RESULTS
  We propagated the specific quaternary structure of Aβ1-40 E22Δ fibrils with wild-type Aβ1-40 over up to seven cycles of seeding and fibril elongation. As a result of a 10(7)-fold dilution of the initially present Aβ1-40 E22Δ seeds, the vast majority of fibrils formed after the seventh propagation cycle with Aβ1-40 did not contain a single molecule of Aβ1-40 E22Δ, but still retained the conformation of the initial Aβ1-40 E22Δ seeds. Increased critical concentrations of Aβ1-40 fibrils formed in the presence of Aβ1-40 E22Δ nuclei suggest that these fibrils are less stable than homologously seeded Aβ1-40 fibrils, consistent with a kinetically controlled mechanism of fibril formation.
  
  
  CONCLUSIONS
  The propagation of a distinct Aβ fibril conformation over multiple cycles of seeded fibril growth demonstrates the basic ability of the Aβ peptide to form amyloid strains that in turn may cause phenotypes in Alzheimer's disease.
authors.affiliation: Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Spirig
authors.forename: Oxana
authors.initials: O
authors.lastname: Ovchinnikova
authors.forename: Toni
authors.initials: T
authors.lastname: Vagt
authors.forename: Rudi
authors.initials: R
authors.lastname: Glockshuber
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40)