Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40204, Düsseldorf, Germany.
Department of Physics, University of South Florida, Tampa, FL, 33620, USA.
Angew Chem Int Ed Engl. 2021 Feb 8;60(6):3016-3021. doi: 10.1002/anie.202010098. Epub 2020 Dec 11.
Amyloid-β peptides (Aβ) assemble into both rigid amyloid fibrils and metastable oligomers termed AβO or protofibrils. In Alzheimer's disease, Aβ fibrils constitute the core of senile plaques, but Aβ protofibrils may represent the main toxic species. Aβ protofibrils accumulate at the exterior of senile plaques, yet the protofibril-fibril interplay is not well understood. Applying chemical kinetics and atomic force microscopy to the assembly of Aβ and lysozyme, protofibrils are observed to bind to the lateral surfaces of amyloid fibrils. When utilizing Aβ variants with different critical oligomer concentrations, the interaction inhibits the autocatalytic proliferation of amyloid fibrils by secondary nucleation on the fibril surface. Thus, metastable oligomers antagonize their replacement by amyloid fibrils both by competing for monomers and blocking secondary nucleation sites. The protofibril-fibril interaction governs their temporal evolution and potential to exert specific toxic activities.
淀粉样β肽（Aβ）可组装成刚性的淀粉样纤维和称为 AβO 或原纤维的亚稳态寡聚物。在阿尔茨海默病中，Aβ纤维构成老年斑的核心，但 Aβ原纤维可能代表主要的毒性物质。Aβ原纤维在老年斑的外部积聚，但原纤维-纤维的相互作用尚不清楚。通过将化学动力学和原子力显微镜应用于 Aβ和溶菌酶的组装，观察到原纤维结合到淀粉样纤维的侧表面上。当使用具有不同临界寡聚浓度的 Aβ变体时，该相互作用通过在纤维表面上的二次成核抑制淀粉样纤维的自动催化增殖。因此，亚稳态寡聚物通过与单体竞争和阻止二级成核位点来拮抗其被淀粉样纤维取代。原纤维-纤维相互作用控制着它们的时间演变和发挥特定毒性活性的潜力。
