Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers

Abstract

The amyloid β peptide (Aβ) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aβ1-42 (oAβ1-42) and/or monomeric Aβ1-42 (mAβ1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAβ1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Aβ1-42. The presence of SST14 inhibited Aβ aggregation and masked the ability of several antibodies to detect Aβ. Notably, Aβ1-42, but not Aβ1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Aβ-directed diagnostics and may signify a role of SST14 in the etiology of AD.

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Article and author information

Author details

  1. Hansen Wang

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    Hansen Wang, Holds provisionary US patent on amyloid-beta binding polypeptides based on the results of this study (filing number 62/451,309)..
  2. Lisa D Muiznieks

    Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    No competing interests declared.
  3. Punam Ghosh

    Department of Medical Biophysics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  4. Declan Williams

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  5. Michael Solarski

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  6. Andrew Fang

    Department of Biochemistry, University of Alberta, Edmonton, Canada
    Competing interests
    No competing interests declared.
  7. Alejandro Ruiz-Riquelme

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6581-7132
  8. Régis Pomès

    Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3068-9833
  9. Joel C Watts

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  10. Avi Chakrabartty

    Department of Medical Biophysics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  11. Holger Wille

    Department of Biochemistry, University of Alberta, Edmonton, Canada
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5102-8706
  12. Simon Sharpe

    Molecular Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    No competing interests declared.
  13. Gerold Schmitt-Ulms

    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
    For correspondence
    g.schmittulms@utoronto.ca
    Competing interests
    Gerold Schmitt-Ulms, Holds provisionary US patent on amyloid-beta binding polypeptides based on the results of this study (filing number 62/451,309).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6962-0919

Funding

Canadian Institutes of Health Research

  • Gerold Schmitt-Ulms

Ontario Centres for Excellence

  • Simon Sharpe
  • Gerold Schmitt-Ulms

Alberta Innovates Bio Solutions (201600028)

  • Holger Wille
  • Gerold Schmitt-Ulms

Heart and Stroke Foundation of Canada (G-15-0009148)

  • Simon Sharpe

Canada Foundation for Innovation

  • Gerold Schmitt-Ulms

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The work was performed in strict accordance with University of Toronto animal care and biosafety recommendations. All mice were handled according to procedures approved (AUP4183.3) by the animal care committee at University Health Network overseeing work at the Krembil Discovery Centre (Toronto). The handling of samples and reagents followed biosafety procedures approved (208-S06-2) by the University of Toronto Biosafety Program.

Copyright

© 2017, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hansen Wang
  2. Lisa D Muiznieks
  3. Punam Ghosh
  4. Declan Williams
  5. Michael Solarski
  6. Andrew Fang
  7. Alejandro Ruiz-Riquelme
  8. Régis Pomès
  9. Joel C Watts
  10. Avi Chakrabartty
  11. Holger Wille
  12. Simon Sharpe
  13. Gerold Schmitt-Ulms
(2017)
Somatostatin binds to the human amyloid β peptide and favors the formation of distinct oligomers
eLife 6:e28401.
https://doi.org/10.7554/eLife.28401

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https://doi.org/10.7554/eLife.28401

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