Details

Autor(en) / Beteiligte

• Tian, Yao
• Liu, Jianbo
• Yang, Fadeng
• Lian, Chenshan
• Zhang, Huawei
• Viles, John H.
• Li, Zigang

Titel

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

Ist Teil von

• The FEBS journal, 2022-11, Vol.289 (21), p.6767-6781

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2022

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• 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. Aβ‐induced membrane disruption is crucial to neurotoxicity. We demonstrate that a rationally designed cyclic amyloid surface inhibitor impedes the secondary nucleation process of Aβ and so suppresses membrane disruption. Only oligomers generated via secondary nucleation disrupt membrane integrity and cause cytotoxicity. Our study adds a mechanistic insight to the importance of membrane disruption in cytotoxicity and highlights the therapeutic potential for targeting secondary nucleation processes within Aβ assembly.