Zhao Qinyue, Tao Youqi, Yao Yuxuan, Liu Kaien, Lv Shiran, Cui Bingyao, Xiao Weidi, Cao Tianyi, Li Weidong, Gao Feng, Shen Yong, Wang Chu, Ma Chao, Qiu Wenying, Liu Cong, Li Dan
Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, China.
Nat Chem Biol. 2025 Jun 10. doi: 10.1038/s41589-025-01921-4.
Abnormal aggregation of amyloid-β protein (1-42) (Aβ) is the primary pathology in Alzheimer's disease (AD). Two types of Aβ fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed 'soluble' during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of Aβ fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD.
淀粉样β蛋白（1-42）（Aβ）的异常聚集是阿尔茨海默病（AD）的主要病理特征。在患病人类大脑的不溶性部分已鉴定出两种类型的Aβ纤维。在此，我们报告称，在AD大脑的 Sarkosyl 提取过程中先前被认为“可溶”的部分实际上含有大量淀粉样纤维，其聚集程度比不溶性部分的纤维更松散。使用冷冻电子显微镜（cryo-EM），我们发现了第三种类型（III型）的Aβ纤维，这种纤维偶尔出现在一个AD大脑的可溶性部分而非不溶性部分中。我们还揭示，与正电子发射断层扫描示踪剂AV-45复合的Aβ纤维的冷冻电子显微镜结构显示，I型Aβ纤维中有一个配体结合通道，而III型Aβ纤维中没有。在这个结合通道中，AV-4与垂直结构结合。通过发现这种离体Aβ纤维的新结构多态性，我们的研究突出了AD患者中Aβ纤维显著的结构异质性。
