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Issue 28, 2020
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Molecular chirality mediated amyloid formation on phospholipid surfaces

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Abstract

One of the neuropathological features of Alzheimer's disease (AD) is the misfolding of amyloid-β to form amyloid aggregates, a process highly associated with biological membranes. However, how molecular chirality affects the amyloid formation on phospholipid surfaces has seldom been reported. Here, L- and D-aspartic acid-modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (L-/D-Asp–DPPE) is synthesized to construct chiral phospholipid bilayers. We discover that the L-Asp–DPPE liposomes slightly inhibit the Aβ(1–40) nucleation process but cannot affect the oligomer elongation process. By contrast, the D-Asp–DPPE liposomes strongly inhibit both nucleation and elongation of the peptide. Notably, L- and D-Asp–DPPE liposomes not only have good biocompatibility but can also rescue Aβ(1–40)-aggregation induced cytotoxicity with significant chiral discrimination, in which the cell viability is higher in the presence of D-Asp–DPPE liposomes. Mechanism analysis and molecular dynamics simulation clearly demonstrate that differential electrostatic interactions of Lys16 in Aβ(1–40) with L- or D-Asp on the phospholipid contribute to the remarkable chiral discrimination. This study provides a deeper understanding of the crucial amyloidosis process from the perspective of the chiral interface and reveals that the convergence of D-amino acids with the liposomes might be a feasible route for AD prevention.

Graphical abstract: Molecular chirality mediated amyloid formation on phospholipid surfaces

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Supplementary files

Article information


Submitted
20 Apr 2020
Accepted
24 Jun 2020
First published
25 Jun 2020

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

Chem. Sci., 2020,11, 7369-7378
Article type
Edge Article

Molecular chirality mediated amyloid formation on phospholipid surfaces

X. Wang, C. Wang, H. Chu, H. Qin, D. Wang, F. Xu, X. Ai, C. Quan, G. Li and G. Qing, Chem. Sci., 2020, 11, 7369
DOI: 10.1039/D0SC02212H

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