School of Biological and Chemical Sciences, Queen Mary University of London, UK.
Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, China.
FEBS J. 2022 Nov;289(21):6767-6781. doi: 10.1111/febs.16550. Epub 2022 Jun 19.
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.
抑制淀粉样蛋白-β肽 (Aβ) 聚集是治疗阿尔茨海默病 (AD) 的一种很有前途的策略，因为普遍认为 Aβ 聚集会引发 AD 病理学。原纤维前 Aβ-寡聚物诱导膜破坏，对神经毒性至关重要。我们之前设计了一种叫做环状螺旋淀粉样表面抑制剂 (cHASI) 的短肽，它可以选择性地结合在 Aβ 纤维表面。在这里，我们使用 cHASI 有效地抑制了 Aβ 在脂质膜环境中的表面催化二次成核过程。通过将 Aβ 单体与脂质囊泡孵育，我们表明在 Aβ 组装成淀粉样纤维的过程中，会形成寡聚体，寡聚体明显破坏了脂质双层。值得注意的是，当 Aβ 单体与 cHASI 孵育时，尽管 Aβ 通过初级成核和延伸形成淀粉样纤维，但这条纤维形成途径不会破坏脂质双层。这表明只有在二次表面成核过程中产生的寡聚体才会破坏膜的完整性。细胞毒性测定证实了 cHASI 的保护作用。我们的研究强调了抑制 Aβ 聚集中的二次成核过程而不是抑制所有纤维形成途径的治疗潜力。
