Österlund, N, Moons, R, Ilag, LL et al. (2 more authors) (2019) Native Ion Mobility-Mass Spectrometry Reveals the Formation of β-Barrel Shaped Amyloid-β Hexamers in a Membrane-Mimicking Environment. Journal of the American Chemical Society, 141 (26). pp. 10440-10450. ISSN 0002-7863
Abstract
The mechanisms behind the Amyloid-β (Aβ) peptide neurotoxicity in Alzheimer's disease are intensely studied and under debate. One suggested mechanism is that the peptides assemble in biological membranes to form β-barrel shaped oligomeric pores that induce cell leakage. Direct detection of such putative assemblies and their exact oligomeric states is however complicated by a high level of heterogeneity. The theory consequently remains controversial, and the actual formation of pore structures is disputed. We herein overcome the heterogeneity problem by employing a native mass spectrometry approach and demonstrate that Aβ(1-42) peptides form coclusters with membrane mimetic detergent micelles. The coclusters are gently ionized using nanoelectrospray and transferred into the mass spectrometer where the detergent molecules are stripped away using collisional activation. We show that Aβ(1-42) indeed oligomerizes over time in the micellar environment, forming hexamers with collision cross sections in agreement with a general β-barrel structure. We also show that such oligomers are maintained and even stabilized by addition of lipids. Aβ(1-40) on the other hand form significantly lower amounts of oligomers, which are also of lower oligomeric state compared to Aβ(1-42) oligomers. Our results thus support the oligomeric pore hypothesis as one important cell toxicity mechanism in Alzheimer's disease. The presented native mass spectrometry approach is a promising way to study such potentially very neurotoxic species and how they could be stabilized or destabilized by molecules of cellular or therapeutic relevance.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 09 Jul 2019 10:48 |
Last Modified: | 11 Jul 2019 08:53 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/jacs.9b04596 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:148279 |