Structural reconstruction of individual filaments in Aß42 fibril populations assembled in vitro reveal rare species that resemble ex vivo amyloid polymorphs from human brains
Structural reconstruction of individual filaments in Aß42 fibril populations assembled in vitro reveal rare species that resemble ex vivo amyloid polymorphs from human brains
复制标题
对体外组装的 A42 原纤维群中单个纤维的结构重建揭示了类似于人脑离体淀粉样蛋白多态性的稀有物种
DOI：
10.1101/2023.07.14.549001
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Aubrey L
中科院分区：
文献类型：
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作者：
Aubrey L
结构多态性已被证明与疾病相关的玻璃体和淀粉样纤维。不同的细丝结构从共同的构建块组装的方式仍然不清楚，但组装环境可能是一个关键的决定因素。为了解决这一问题，从原子力显微镜图像中进行了单个纤维结构的三维重建，以绘制在最常用的缓冲液条件下体外形成的Aβ 42淀粉样蛋白原纤维群体的结构多态性景观。数据显示Aβ 42纤丝多态性对组装环境的异质性程度和形成的纤丝种类的敏感性。然而，在整个实验条件下观察到一些保守的原纤维多晶型物。令人兴奋的是，通过将单个细丝结构与冷冻电子显微镜获得的结构数据相匹配，在这些异质群体云中发现了与从人类患者大脑中纯化的Aβ 42淀粉样蛋白多态性显着相似的罕见物种。这些结果将体外实验方法与体内形成的结构联系起来，并突出了多晶型分布，以及这些异质分子分布中结构变化的类型和幅度作为淀粉样蛋白生物学的重要因素。
Structural polymorphism has been demonstrated for bothin vitroandex vivoamyloid fibrils associated with disease. The manner in which different filament structures are assembled from common building blocks remains unclear but the assembly environment is likely to be a key determinant. To address this, three-dimensional reconstruction of individual filament structures was conducted from atomic force microscopy images to map the structural polymorphism landscape of Aβ42amyloid fibril populations formedin vitrounder most frequently used buffer conditions. The data show sensitivity of Aβ42fibril polymorphism to the assembly environment in both the magnitude of heterogeneity and the types of filament species formed. However, some conserved fibril polymorphs were observed across the experimental conditions. Excitingly, by matching individual filament structures to cryo-electron microscopy derived structural data, rare species in these heterogeneous population clouds that show remarkable similarity to Aβ42amyloid polymorphs purified from human patient brains were discovered. These results linkin vitroexperimental approaches with structures formedin vivo, and highlight the polymorph distribution, and the type and magnitude of structural variations within these heterogeneous molecular distributions as important factors in amyloid biology.