Amyloid fibrils represent a pathological state of protein polymer that is closely associated with various neurodegenerative diseases. Polysaccharides have a prominent role in recognizing amyloid fibrils and mediating their pathogenicity. However, the mechanism underlying the amyloid–polysaccharide interaction remains elusive. We also do not know its impact on the structure and pathology of formed fibrils. Here, we used cryo-electron microscopy to analyze the atomic structures of mature α-synuclein (α-syn) fibrils upon binding with polymeric heparin and heparin-like oligosaccharides. The fibril structure, including the helical twist and conformation of α-syn, changed over time upon the binding of heparin but not oligosaccharides. The sulfation pattern and numbers of saccharide units are important for the binding. Similarly, negatively charged biopolymers typically interact with amyloid fibrils, including tau and various α-syn polymorphs, leading to alterations in their conformation. Moreover, we show that heparin-like oligosaccharides can not only block neuronal uptake and propagation of formed α-syn fibrils but also inhibit α-syn fibrillation. This work demonstrates a distinctive activity of heparin and biopolymers in remodeling amyloid fibrils and suggests the pharmaceutical potential of heparin-like oligosaccharides.

淀粉样蛋白原纤维代表蛋白质聚合物的一种病理状态，与各种神经退行性疾病密切相关。多糖在识别淀粉样原纤维和介导其致病性方面起着重要作用。然而，淀粉样蛋白-多糖相互作用的潜在机制仍然难以捉摸。我们也不知道它对形成的原纤维的结构和病理学的影响。在这里，我们使用冷冻电子显微镜分析了成熟 α-突触核蛋白 （α-syn） 原纤维与聚合物肝素和肝素样寡糖结合时的原子结构。原纤维结构，包括 α-syn 的螺旋扭曲和构象，在与肝素结合时随时间变化，但与寡糖结合时没有变化。硫酸化模式和糖单位的数量对于结合很重要。同样，带负电荷的生物聚合物通常与淀粉样蛋白原纤维相互作用，包括 tau 和各种 α-syn 多晶型物，导致其构象发生变化。此外，我们表明肝素样寡糖不仅可以阻断神经元摄取和形成的 α-syn 原纤维的传播，还可以抑制 α-syn 原纤维化。这项工作证明了肝素和生物聚合物在重塑淀粉样蛋白原纤维方面的独特活性，并表明肝素样寡糖的制药潜力。