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A novel Aβ40 assembly at physiological concentration

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Title: A novel Aβ40 assembly at physiological concentration
Authors: Ying, L
Tahirbegi, B
Magness, A
Piersimoni, M
Knopfel, T
Willison, K
Klug, D
Item Type: Journal Article
Abstract: Aggregates of amyloid-β (Aβ) are characteristic of Alzheimer’s disease, but there is no consensus as to either the nature of the toxic molecular complex or the mechanism by which toxic aggregates are produced. We report on a novel feature of amyloid-lipid interactions where discontinuities in the lipid continuum can serve as catalytic centers for a previously unseen microscale aggregation phenomenon. We show that specific lipid membrane conditions rapidly produce long contours of lipid-bound peptide, even at sub-physiological concentrations of Aβ. Using single molecule fluorescence, time-lapse TIRF microscopy and AFM imaging we characterize this phenomenon and identify some exceptional properties of the aggregation pathway which make it a likely contributor to early oligomer and fibril formation, and thus a potential critical mechanism in the etiology of AD. We infer that these amyloidogenic events occur only at areas of high membrane curvature, which suggests a range of possible mechanisms by which accumulated physiological changes may lead to their inception. The speed of the formation is in hours to days, even at 1 nM peptide concentrations. Lipid features of this type may act like an assembly line for monomeric and small oligomeric subunits of Aβ to increase their aggregation states. We conclude that under lipid environmental conditions, where catalytic centers of the observed type are common, key pathological features of AD may arise on a very short timescale under physiological concentration.
Issue Date: 11-Jun-2020
Date of Acceptance: 15-May-2020
URI: http://hdl.handle.net/10044/1/80475
DOI: 10.1038/s41598-020-66373-3
ISSN: 2045-2322
Publisher: Nature Publishing Group
Journal / Book Title: Scientific Reports
Volume: 10
Copyright Statement: © 2020 The Authors. 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/.
Sponsor/Funder: The Leverhulme Trust
Funder's Grant Number: RPG-2015-345
Publication Status: Published
Article Number: 9477
Online Publication Date: 2020-06-11
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
National Heart and Lung Institute
Department of Medicine (up to 2019)
Department of Brain Sciences
Faculty of Natural Sciences