title: Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils.
abstract: Several lines of evidence indicate that prefibrillar assemblies of amyloid-β (Aβ) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimer's disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Aβ fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aβ peptides and stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Aβ oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Aβ oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.
authors.affiliation: Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Bieschke
authors.forename: Martin
authors.initials: M
authors.lastname: Herbst
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiglenda
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Friedrich
authors.forename: Annett
authors.initials: A
authors.lastname: Boeddrich
authors.forename: Franziska
authors.initials: F
authors.lastname: Schiele
authors.forename: Daniela
authors.initials: D
authors.lastname: Kleckers
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Lopez del Amo
authors.forename: Björn A
authors.initials: BA
authors.lastname: Grüning
authors.forename: Qinwen
authors.initials: Q
authors.lastname: Wang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schmidt
authors.forename: Rudi
authors.initials: R
authors.lastname: Lurz
authors.forename: Roger
authors.initials: R
authors.lastname: Anwyl
authors.forename: Sigrid
authors.initials: S
authors.lastname: Schnoegl
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Frank
authors.forename: Bernd
authors.initials: B
authors.lastname: Reif
authors.forename: Stefan
authors.initials: S
authors.lastname: Günther
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D045744:Cell Line, Tumor; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D010078:Oxazines / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D009435:Synaptic Transmission
chemical_list: D000682:Amyloid; C569778:O4 compound; D010078:Oxazines; D010446:Peptide Fragments
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