Amyloidosis is characterized by the abnormal accumulation of amyloid proteins. The causative proteins aggregate from monomers to oligomers and fibrils, among which some intermediate oligomers considered as major toxins. Cytotoxic oligomers are generated not only by aggregation but also via fibril disaggregation. However, little is known about the structural characteristics and generation conditions of cytotoxic oligomers produced during disaggregation. Herein, we summarized the structural commonalities of cytotoxic oligomers formed under various disaggregation conditions, including the addition of heat shock proteins or small compounds. In vitro experimental data demonstrated the presence of high-molecular-weight oligomers (protofibrils or protofilaments) that exhibited a fibrous morphology and β-sheet structure. Molecular dynamics simulations indicated that the distorted β-sheet structure contributed to their metastability. The tendency of these cytotoxic oligomers to appear under mild disaggregation conditions, implied formation during the early stages of disaggregation. This review will aid researchers in exploring the characteristics of highly cytotoxic oligomers and developing drugs that target amyloid aggregates.

中文翻译：

---

解聚过程中产生的细胞毒性淀粉样蛋白寡聚体的结构

淀粉样变性的特征是淀粉样蛋白的异常积累。致病蛋白从单体聚集成寡聚体和原纤维，其中一些中间寡聚体被认为是主要毒素。细胞毒性低聚物不仅通过聚集产生，还通过原纤维解聚产生。然而，人们对解聚过程中产生的细胞毒性寡聚物的结构特征和生成条件知之甚少。在此，我们总结了在各种解聚条件下形成的细胞毒性寡聚物的结构共性，包括添加热休克蛋白或小化合物。体外实验数据证明存在高分子量低聚物（原纤维或原丝），其表现出纤维形态和β-折叠结构。分子动力学模拟表明，扭曲的β-折叠结构有助于其亚稳定性。这些细胞毒性低聚物在温和解聚条件下出现的趋势表明在解聚的早期阶段就形成了。这篇综述将帮助研究人员探索高细胞毒性寡聚物的特征并开发针对淀粉样蛋白聚集体的药物。