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

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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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.

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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  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
(2020)
Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer disease related oligomers
eLife 9:e59306.
https://doi.org/10.7554/eLife.59306

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https://doi.org/10.7554/eLife.59306