Novel Mechanistic Insight into the Molecular Basis of Amyloid Polymorphism and Secondary Nucleation during Amyloid Formation
Novel Mechanistic Insight into the Molecular Basis of Amyloid Polymorphism and Secondary Nucleation during Amyloid Formation
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DOI：
10.1016/j.jmb.2013.02.005
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发表时间：
2013-05-27
影响因子：
5.6
通讯作者：
Dietler, Giovanni
中科院分区：
文献类型：
--
作者：
Jeong, Jae Sun;Ansaloni, Annalisa;Dietler, Giovanni
淀粉样蛋白β（A β）纤维的形成在引发最终导致阿尔茨海默病的病理事件级联中至关重要。在这项研究中，我们研究了在受控聚集条件下从流体动力学定义良好的物种形成A β原纤维的机制。我们提出了一个详细的机制模型，阐明了一个新的洞察A β 42纤维形成的过程和淀粉样蛋白途径中的不同结构转换的分子基础。我们的数据揭示了A β原纤维的结构和多态性受到起始材料的低聚状态、A β 42的单体与聚集形式（低聚物和原纤维）的比率以及次级成核的发生的严重影响。我们证明，单体A β 42在介导淀粉样蛋白途径中的结构转变中起着重要作用，并首次提供证据表明，A β 42通过成核聚合和二次成核的组合机制发生纤维化。这些发现将对我们理解体内淀粉样蛋白形成的分子基础、A β病理学的异质性（例如，弥漫性与淀粉样斑块），以及A β毒性的结构基础。(C)2013爱思唯尔有限公司保留所有权利。
The formation of amyloid beta (A beta) fibrils is crucial in initiating the cascade of pathological events that culminates in Alzheimer's disease. In this study, we investigated the mechanism of A beta fibril formation from hydrodynamically well defined species under controlled aggregation conditions. We present a detailed mechanistic model that furnishes a novel insight into the process of A beta 42 fibril formation and the molecular basis for the different structural transitions in the amyloid pathway. Our data reveal the structure and polymorphism of A beta fibrils to be critically influenced by the oligomeric state of the starting materials, the ratio of monomeric-to-aggregated forms of A beta 42 (oligomers and protofibrils), and the occurrence of secondary nucleation. We demonstrate that monomeric A beta 42 plays an important role in mediating structural transitions in the amyloid pathway, and for the first time, we provide evidences that A beta 42 fibrillization occurs via a combined mechanism of nucleated polymerization and secondary nucleation. These findings will have significant implications to our understanding of the molecular basis of amyloid formation in vivo, of the heterogeneity of A beta pathology (e.g., diffuse versus amyloid plaques), and of the structural basis of A beta toxicity. (C) 2013 Elsevier Ltd. All rights reserved.