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Issue 24, 2019
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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

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Publication details

The article was received on 19 Mar 2019, accepted on 19 May 2019 and first published on 21 May 2019


Article type: Edge Article
DOI: 10.1039/C9SC01331H
Chem. Sci., 2019,10, 6072-6082
  • Open access: Creative Commons BY license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    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

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