Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
Paulson School of Engineering and Applied Science, Harvard University, Cambridge, MA, USA.
Nat Chem. 2020 May;12(5):445-451. doi: 10.1038/s41557-020-0452-1. Epub 2020 Apr 13.
Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer's disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.
寡聚体物种在 Aβ42 肽聚集过程中被确定为与阿尔茨海默病相关的有效细胞毒素，但控制其动力学的基本分子途径尚未阐明。通过开发一种结合理论、实验和模拟的通用方法，我们详细揭示了 Aβ42 寡聚体在淀粉样纤维形成过程中的动力学机制。尽管所有成熟的淀粉样纤维都必须起源于寡聚体，但我们发现大多数 Aβ42 寡聚体在不形成新纤维的情况下解离成其单体前体。只有少数寡聚体转化为纤维状结构。此外，寡聚体物种的异构混合物在与聚集相当的时间尺度上相互转化。我们的研究结果确定了一些新的基本步骤，这些步骤可能成为针对蛋白质错误折叠疾病的治疗干预的目标。
