Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer disease related oligomers
- Goethe-University, Germany
- University of Duisburg-Essen, Germany
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
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
- John Kuriyan, University of California, Berkeley, United States
Version history
- Received: May 25, 2020
- Accepted: October 22, 2020
- Accepted Manuscript published: October 23, 2020 (version 1)
- 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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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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