1. Neuroscience
Download icon

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
  • Views 1,108
  • Annotations
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.

Data availability

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.

Metrics

  • 1,108
    Page views
  • 180
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Developmental Biology
    2. Neuroscience

    Spinal lumbar dI2 interneurons contribute to stability of bipedal stepping

    Baruch Haimson et al.
    Research Article Updated

    Peripheral and intraspinal feedback is required to shape and update the output of spinal networks that execute motor behavior. We report that lumbar dI2 spinal interneurons in chicks receive synaptic input from afferents and premotor neurons. These interneurons innervate contralateral premotor networks in the lumbar and brachial spinal cord, and their ascending projections innervate the cerebellum. These findings suggest that dI2 neurons function as interneurons in local lumbar circuits, are involved in lumbo-brachial coupling, and that part of them deliver peripheral and intraspinal feedback to the cerebellum. Silencing of dI2 neurons leads to destabilized stepping in posthatching day 8 hatchlings, with occasional collapses, variable step profiles, and a wide-base walking gait, suggesting that dI2 neurons may contribute to the stabilization of the bipedal gait.

    1. Cell Biology
    2. Neuroscience

    Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration

    Rene Solano Fonseca et al.
    Research Article Updated

    Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect.

    1. Biochemistry and Chemical Biology
    2. Neuroscience

    Precise optical control of gene expression in C elegans using improved genetic code expansion and Cre recombinase

    Lloyd Davis et al.
    Tools and Resources Updated

    Synthetic strategies for optically controlling gene expression may enable the precise spatiotemporal control of genes in any combination of cells that cannot be targeted with specific promoters. We develop an improved genetic code expansion system in Caenorhabditis elegans and use it to create a photoactivatable Cre recombinase. We laser-activate Cre in single neurons within a bilaterally symmetric pair to selectively switch on expression of a loxP-controlled optogenetic channel in the targeted neuron. We use the system to dissect, in freely moving animals, the individual contributions of the mechanosensory neurons PLML/PLMR to the C. elegans touch response circuit, revealing distinct and synergistic roles for these neurons. We thus demonstrate how genetic code expansion and optical targeting can be combined to break the symmetry of neuron pairs and dissect behavioural outputs of individual neurons that cannot be genetically targeted.