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Issue 24, 2019

Atomic resolution map of the soluble amyloid beta assembly toxic surfaces

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Abstract

Soluble amyloid beta assemblies (Aβn) are neurotoxic and play a central role in the early phases of the pathogenesis cascade leading to Alzheimer's disease. However, the current knowledge about the molecular determinants of Aβn toxicity is at best scant. Here, we comparatively analyze Aβn prepared in the absence or presence of a catechin library that modulates cellular toxicity. By combining solution NMR with dynamic light scattering, fluorescence spectroscopy, electron microscopy, wide-angle X-ray diffraction and cell viability assays, we identify a cluster of unique molecular signatures that distinguish toxic vs. nontoxic Aβ assemblies. These include the exposure of a hydrophobic surface spanning residues 17–28 and the concurrent shielding of the highly charged N-terminus. We show that the combination of these two dichotomous structural transitions promotes the colocalization and insertion of β-sheet rich Aβn into the membrane, compromising membrane integrity. These previously elusive toxic surfaces mapped here provide an unprecedented foundation to establish structure-toxicity relationships of Aβ assemblies.

Graphical abstract: Atomic resolution map of the soluble amyloid beta assembly toxic surfaces

Supplementary files

Article information


Submitted
19 Mar 2019
Accepted
19 May 2019
First published
21 May 2019

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2019,10, 6072-6082
Article type
Edge Article

Atomic resolution map of the soluble amyloid beta assembly toxic surfaces

R. Ahmed, M. Akcan, A. Khondker, M. C. Rheinstädter, J. C. Bozelli, R. M. Epand, V. Huynh, R. G. Wylie, S. Boulton, J. Huang, C. P. Verschoor and G. Melacini, Chem. Sci., 2019, 10, 6072 DOI: 10.1039/C9SC01331H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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