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Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer disease related oligomers

  1. Tobias Lieblein
  2. Rene Zangl
  3. Janosch Martin
  4. Jan Hoffmann
  5. Marie J Hutchison
  6. Tina Stark
  7. Elke Stirnal
  8. Thomas Schrader
  9. Harald Schwalbe
  10. Nina Morgner  Is a corresponding author
  1. Goethe-University, Germany
  2. University of Duisburg-Essen, Germany
Research Article
  • Cited 2
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Cite this article as: eLife 2020;9:e59306 doi: 10.7554/eLife.59306

Abstract

The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.

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All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Tobias Lieblein

    Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6497-1733
  2. Rene Zangl

    Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Janosch Martin

    Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Jan Hoffmann

    Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Marie J Hutchison

    Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt am Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Tina Stark

    Institute for Organic Chemistry and Chemical Biology, Goethe-University, Frankfurt am Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Elke Stirnal

    Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt am Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Thomas Schrader

    Department of Chemistry, University of Duisburg-Essen, Essen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Harald Schwalbe

    Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt am Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Nina Morgner

    Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany
    For correspondence
    morgner@chemie.uni-frankfurt.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1872-490X

Funding

Deutsche Forschungsgemeinschaft (GRK1986)

  • Nina Morgner

LOEWE Schwerpunkt from State of Hesse (GLUE)

  • Nina Morgner

Cluster of Excellence Frankfurt (MacromolecularComplexes)

  • Nina Morgner

Deutsche Forschungsgemeinschaft (Heisenbergprofessorship)

  • Nina Morgner

Deutsche Forschungsgemeinschaft (CRC1093)

  • Thomas Schrader

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

Reviewing Editor

  1. John Kuriyan, University of California, Berkeley, United States

Publication history

  1. Received: May 25, 2020
  2. Accepted: October 22, 2020
  3. Accepted Manuscript published: October 23, 2020 (version 1)
  4. Version of Record published: November 23, 2020 (version 2)

Copyright

© 2020, Lieblein 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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