Therapeutic potential for amyloid surface inhibitor: only amyloid-β oligomers formed by secondary nucleation disrupt lipid membrane integrity.

Inhibition of amyloid-β peptide (Aβ) aggregation is a promising therapeutic strategy for Alzheimer's disease (AD), as Aβ aggregation is generally believed to trigger AD pathology. Pre-fibril Aβ-oligomers induce membrane disruption and are crucial to neurotoxicity. We have previously designed a short peptide called cyclic helical amyloid surface inhibitor (cHASI) that can selectively bind to the Aβ fibril surface. Here, we use cHASI to efficiently inhibit the surface-catalysed secondary nucleation process of Aβ in a lipid membrane environment. By incubating Aβ monomers with lipid vesicles, we show that during the assembly of Aβ into amyloid fibrils, oligomers are formed that markedly disrupt the lipid bilayer. Remarkably, when Aβ monomers are incubated with cHASI, although Aβ forms amyloid fibrils via primary nucleation and elongation, this pathway to fibrils does not damage the lipid bilayer. This indicates that only oligomers produced during secondary surface nucleation disrupt membrane integrity. The protective effect of cHASI is confirmed by cytotoxicity assays. Our study highlights the therapeutic potential for inhibiting the secondary nucleation process in Aβ aggregation, rather than inhibiting all pathways to fibril formation.