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

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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

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Tobias Lieblein

Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6497-1733
Rene Zangl

Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Janosch Martin

Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Jan Hoffmann

Institute of Physical and Theoretical Chemistry, Goethe-University, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Marie J Hutchison

Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt am Main, Germany

Competing interests
The authors declare that no competing interests exist.
Tina Stark

Institute for Organic Chemistry and Chemical Biology, Goethe-University, Frankfurt am Main, Germany

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The authors declare that no competing interests exist.
Elke Stirnal

Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt am Main, Germany

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The authors declare that no competing interests exist.
Thomas Schrader

Department of Chemistry, University of Duisburg-Essen, Essen, Germany

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The authors declare that no competing interests exist.
Harald Schwalbe

Center for Biomolecular Magnetic Resonance, Goethe-University, Frankfurt am Main, Germany

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The authors declare that no competing interests exist.
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.

"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.

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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.