Molecular chirality mediated amyloid formation on phospholipid surfaces

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.