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

  • 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:Tobias LiebleinORCiDGND, Rene ZanglORCiD, Janosch MartinGND, Jan HoffmannORCiDGND, Marie J. Hutchison, Tina Stark, Elke Stirnal, Thomas Schrader, Harald SchwalbeORCiDGND, Nina MorgnerORCiDGND
Parent Title (English):eLife
Publisher:eLife Sciences Publications
Place of publication:Cambridge
Document Type:Article
Date of Publication (online):2020/10/23
Date of first Publication:2020/10/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/08/03
Issue:art. e59306
Page Number:27
First Page:1
Last Page:27
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0