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Small-molecule conversion of toxic oligomers to nontoxic β-sheet–rich amyloid fibrils

Nature Chemical Biology volume 8, pages 93–101 (2012)Cite this article

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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.

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Figure 1: Identification and characterization of compounds that accelerate Aβ42 aggregation.
Figure 2: O4 binds to Aβ42 oligomers and stimulates their conversion into SDS-stable fibrils.
Figure 3: O4 binds to hydrophobic regions in Aβ peptides.
Figure 4: O4 changes the binding of anti-Aβ antibodies to amyloid fibrils.
Figure 5: O4 binds to hydrophobic grooves on the surface of β-sheet–rich Aβ42 fibrils.
Figure 6: O4 reduces Aβ42 toxicity and improves synaptic transmission.
Figure 7: Working model of effects of O4 on spontaneous Aβ42 polymerization.

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Acknowledgements

We thank S. Kostka, G. Grelle and S. Rautenberg for technical assistance; A. Otto for analysis of compound mixtures by MS; and M. Peters for expert discussions. The research leading to these results has received funding from the European Commission FP7 grants EUROSPIN (241498) and SYNSYS (242167) and from the European Integrated Projects APOPIS (503330) and EUROSCA (503304) as well as from the Initiative and Networking Fund of the Helmholtz Association (MSBN, TP3, TP5) and the Helmholtz Alliance for Mental Health in an Ageing Society to E.E.W. Furthermore, this work was supported by grants from Deutsche Forschungsgemeinschaft (DFG) (WA 1151/5), Bundesministerium für Bildung und Forschung (BMBF) (NGFN1, 01KW0015; NGFN2, 01GR0471; BioFuture, 0311853; GO-Bio, 0313881) to E.E.W., BMBF (NGFN-Plus, 01GS08132) to J.B. and E.E.W. and DFG (BI 1409/2-1) to J.B.

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Author notes

  1. Jan Bieschke & Qinwen Wang

    Present address: Present addresses: Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA (J.B.) and Department of Physiology and Pharmacology, Medical School, Ningbo University, Ningbo, China (Q.W.).,

  2. Jan Bieschke and Martin Herbst: These authors contributed equally to this work.

Authors and Affiliations

  1. Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Berlin, Germany

    Jan Bieschke, Martin Herbst, Thomas Wiglenda, Ralf P Friedrich, Annett Boeddrich, Franziska Schiele, Daniela Kleckers, Michael R Schmidt, Sigrid Schnoegl & Erich E Wanker

  2. Department of Neurology, Charité-Universitätsmedizin Berlin, Germany

    Martin Herbst

  3. Helmholtz Centre for Infection Research, Braunschweig, Germany

    Juan Miguel Lopez del Amo & Bernd Reif

  4. Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Freiburg, Germany

    Björn A Grüning & Stefan Günther

  5. Department of Physiology, School of Medicine, Trinity College, Dublin, Republic of Ireland

    Qinwen Wang & Roger Anwyl

  6. Max Planck Institute for Molecular Genetics, Berlin, Germany

    Rudi Lurz

  7. Max Planck Research Unit for Enzymology of Protein Folding, Halle (Saale), Germany

    Marcus Fändrich

  8. Department of Chemistry, Helmholtz Center for Infection Research, Braunschweig, Germany

    Ronald F Frank

  9. Technical University Munich, Munich, Germany

    Bernd Reif

  10. Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Republic of Ireland

    Dominic M Walsh

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Contributions

M.H., J.B., R.P.F., A.B., F.S., D.K. and M.R.S. performed aggregation experiments; T.W. provided chemistry expertise; J.M.L. and B.R. performed NMR experiments; B.A.G. and S.G. performed computational docking studies; Q.W., R.A. and D.M.W. contributed LTP experiments; R.L. helped with EM; M.F. contributed a conformation-specific antibody; R.F.F. produced peptide arrays; S.S., J.B. and E.E.W. edited the manuscript; E.E.W. designed the study and wrote the manuscript.

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Correspondence to Erich E Wanker.

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Bieschke, J., Herbst, M., Wiglenda, T. et al. Small-molecule conversion of toxic oligomers to nontoxic β-sheet–rich amyloid fibrils. Nat Chem Biol 8, 93–101 (2012). https://doi.org/10.1038/nchembio.719

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