Molecular chirality mediated amyloid formation on phospholipid surfaces

One of the neuropathological features of Alzheimer's disease (AD) is 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 is seldom reported. Here, L- and D-Aspartic acid−modified 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (L-/D-Asp-DPPE) are synthesized to construct chiral phospholipid bilayers. We discover that the L-Asp-DPPE liposomes slightly inhibit Aβ(1−40) nucleation process but cannot affect 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 also can 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 interaction of Lys16 in Aβ(1−40) with L- or D-Asp on the phospholipid contributes to the remarkable chiral discrimination. This study provides deeper understanding of the crucial amyloidosis process from the perspective of chiral interface, while reveals that the convergence of D-amino acids with the liposomes might be a feasible route for AD prevention.