Cryo-EM Analysis of the Effect of Seeding with Brain-derived Aβ Amyloid Fibrils.
Cryo-EM Analysis of the Effect of Seeding with Brain-derived Aβ Amyloid Fibrils.
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冷冻电镜分析脑源性 Aβ 淀粉样原纤维播种效果。
DOI：
10.1016/j.jmb.2023.168422
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发表时间：
2024
影响因子：
5.6
通讯作者：
Fändrich,Marcus
中科院分区：
文献类型：
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作者：
Pfeiffer,PeterBenedikt;Ugrina,Marijana;Schwierz,Nadine;Sigurdson,ChristinaJ;Schmidt,Matthias;Fändrich,Marcus
来自阿尔茨海默病脑组织的 Aβ 淀粉样原纤维具有多态性，并且在结构上与典型的体外形成的 Aβ 原纤维不同。在这里，我们证明脑源性（离体）原纤维结构可以通过体外接种来增殖。增殖反应仅对三种丰富的离体Aβ原纤维形态之一有效，其由两个肽堆叠组成，而低效增殖的原纤维形态包含四个或六个肽堆叠。除了接种原纤维结构之外，我们发现如果接种反应持续多代，则在接种样品中可以出现从头有核原纤维结构。这些数据意味着从头成核和种子延伸之间存在竞争，并进一步表明播种有利于含有较少肽堆叠的原纤维形态的生长。
Aβ amyloid fibrils from Alzheimer’s brain tissue are polymorphic and structurally different from typical in vitro formed Aβ fibrils. Here, we show that brain-derived (ex vivo) fibril structures can be proliferated by seeding in vitro. The proliferation reaction is only efficient for one of the three abundant ex vivo Aβ fibril morphologies, which consists of two peptide stacks, while the inefficiently proliferated fibril morphologies contain four or six peptide stacks. In addition to the seeded fibril structures, we find that de novo nucleated fibril structures can emerge in seeded samples if the seeding reaction is continued over multiple generations. These data imply a competition between de novo nucleation and seed extension and suggest further that seeding favours the outgrowth of fibril morphologies that contain fewer peptide stacks.