英国医学研究委员会分子生物学实验室Michel Goedert、Sjors H. W. Scheres、Benjamin Ryskeldi-Falcon以及美国印第安纳大学Bernardino Ghetti研究团队合作取得一项新突破。他们揭示人脑淀粉样蛋白-β 42丝的冷冻电镜(cryo-EM)结构。2022年1月14日，国际知名学术期刊《科学》发表了这一成果。

他们报告了来自人脑的残基 42 (Aβ42)细丝的冷冻电镜结构。两个结构相关的 S 形原丝折叠产生两种类型的纤维。I 型纤维主要存在于散发性阿尔茨海默病患者的大脑中，而 II 型纤维则存在于家族性阿尔茨海默病和其他疾病患者的大脑中。来自大脑的 Aβ42 纤维的结构与体外组装的纤维不同。相比之下，在 AppNL-F 敲入小鼠中，Aβ42 沉积物由 II 型纤维构成。 对人脑 Aβ42 纤维结构的了解可能会导致组装抑制剂和改进成像剂的开发。

据介绍，在Aβ42处结束的淀粉样蛋白-β 肽的纤维组装是阿尔茨海默病的核心事件。

附：英文原文

Title: Cryo-EM structures of amyloid-β 42 filaments from human brains

Author: Yang Yang, Diana Arseni, Wenjuan Zhang, Melissa Huang, Sofia Lvestam, Manuel Schweighauser, Abhay Kotecha, Alexey G. Murzin, Sew Y. Peak-Chew, Jennifer Macdonald, Isabelle Lavenir, Holly J. Garringer, Ellen Gelpi, Kathy L. Newell, Gabor G. Kovacs, Ruben Vidal, Bernardino Ghetti, Benjamin Ryskeldi-Falcon, Sjors H. W. Scheres, Michel Goedert

Issue&Volume: 2022-01-14

Abstract: Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.

DOI: abm7285

Source: https://www.science.org/doi/10.1126/science.abm7285