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Pre\u2010fibril A\u03b2\u2010oligomers 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 A\u03b2 fibril surface. Here, we use cHASI to efficiently inhibit the surface\u2010catalysed secondary nucleation process of A\u03b2 in a lipid membrane environment. By incubating A\u03b2 monomers with lipid vesicles, we show that during the assembly of A\u03b2 into amyloid fibrils, oligomers are formed that markedly disrupt the lipid bilayer. Remarkably, when A\u03b2 monomers are incubated with cHASI, although A\u03b2 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 A\u03b2 aggregation, rather than inhibiting all pathways to fibril formation.<\/jats:p>","DOI":"10.1111\/febs.16550","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T13:13:44Z","timestamp":1654607624000},"page":"6767-6781","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Therapeutic potential for amyloid surface inhibitor: only amyloid\u2010\u03b2 oligomers formed by secondary nucleation disrupt lipid membrane integrity"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5510-0947","authenticated-orcid":false,"given":"Yao","family":"Tian","sequence":"first","affiliation":[{"name":"School of Biological and Chemical Sciences Queen Mary University of London  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