Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

Abstract

Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer’s disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer’s disease.

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Item Type:	Article
Authors/Creators:	De, S. https://orcid.org/0000-0003-1675-0773 Wirthensohn, D.C. Flagmeier, P. Hughes, C. Aprile, F.A. Ruggeri, F.S. Whiten, D.R. Emin, D. Xia, Z. Varela, J.A. Sormanni, P. Kundel, F. Knowles, T.P.J. Dobson, C.M. Bryant, C. Vendruscolo, M. Klenerman, D.
Copyright, Publisher and Additional Information:	© The Author(s) 2019. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Amyloid beta-Peptides; Animals; Cell Membrane Permeability; Lipid Bilayers; Mice; Microglia; Protein Aggregation, Pathological; Ultracentrifugation
Dates:	Accepted: 13 March 2019 Published (online): 4 April 2019 Published: 4 April 2019
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	04 May 2020 13:45
Last Modified:	04 May 2020 14:20
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-019-09477-3
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:160176

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Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

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