Protein amyloid aggregation is a hallmark in neuropathologies and other diseases of tremendous impact such as Alzheimer's or Parkinson's diseases. During the last decade, it has become increasingly evident that neuronal death is mainly induced by proteinaceous oligomers rather than the mature amyloid fibrils. Therefore, the earliest molecular events occurring during the amyloid aggregation cascade represent a growing interest of study. Important breakthroughs have been achieved using experimental data from different proteins, used as models, as well as systems related to diseases. Here, we summarize the structural properties of amyloid oligomeric and fibrillar aggregates and review the recent advances on how biophysical techniques can be combined with quantitative kinetic analysis and theoretical models to study the detailed mechanism of oligomer formation and nucleation of fibrils. These insights into the mechanism of early oligomerization and amyloid nucleation are of relevant interest in drug discovery and in the design of preventive strategies against neurodegenerative diseases.

中文翻译：

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模型和疾病相关蛋白中淀粉样原纤维成核的早期机制。

蛋白质淀粉样蛋白聚集是神经病理学和其他影响巨大的疾病（例如阿尔茨海默氏病或​​帕金森氏病）的标志。在过去的十年中，越来越明显的是，神经元死亡主要是由蛋白质类寡聚物而不是成熟的淀粉样蛋白原纤维引起的。因此，在淀粉样蛋白聚集级联过程中发生的最早的分子事件代表了越来越多的研究兴趣。使用来自不同蛋白质的实验数据（用作模型以及与疾病相关的系统）已经实现了重要突破。这里，我们总结了淀粉样蛋白低聚体和原纤维聚集体的结构特性，并综述了如何将生物物理技术与定量动力学分析和理论模型相结合以研究低聚物形成和原纤维成核的详细机理的最新进展。这些对早期低聚和淀粉样蛋白成核机制的见解在药物发现和针对神经退行性疾病的预防策略设计中具有重要意义。