Unraveling Alzheimer’s complexity with a distinct Aβ42 fibril type and specific AV-45 binding

IF 12.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nature chemical biology Pub Date : 2025-06-10 DOI:10.1038/s41589-025-01921-4

Qinyue Zhao, Youqi Tao, Yuxuan Yao, Kaien Liu, Shiran Lv, Bingyao Cui, Weidi Xiao, Tianyi Cao, Weidong Li, Feng Gao, Yong Shen, Chu Wang, Chao Ma, Wenying Qiu, Cong Liu, Dan Li

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Abstract

Abnormal aggregation of amyloid-β protein (1–42) (Aβ₄₂) is the primary pathology in Alzheimer’s disease (AD). Two types of Aβ₄₂ 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 Aβ₄₂ fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ₄₂ fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ₄₂ fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ₄₂ fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD.

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揭示阿尔茨海默氏症的复杂性与独特的a β42纤维类型和特异性AV-45结合

淀粉样蛋白-β (1-42) （a -β 42）异常聚集是阿尔茨海默病（AD）的主要病理。两种类型的Aβ42原纤维已经在患病人脑的不溶性部分中被鉴定出来。在这里，我们报告说，在萨科齐法提取阿尔茨海默病脑的过程中，以前被认为是“可溶”的部分实际上含有许多淀粉样蛋白原纤维，其束束比不溶部分更松散。使用低温电子显微镜（cryo-EM），我们发现了第三种类型（III型）的a β42原纤维，偶尔在一个AD大脑的可溶部分中发现，但不是不可溶部分。我们还发现，与正电子发射断层扫描示踪剂AV-45配合的a β42原纤维的低温电镜结构显示，a β42原纤维的I型中存在配体结合通道，而III型中没有。在这个结合通道中，AV-45与垂直几何体接合。通过这种体外Aβ42原纤维结构多态性的发现，我们的研究强调了AD患者Aβ42原纤维结构的显著异质性。

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来源期刊

Nature chemical biology 生物-生化与分子生物学

CiteScore

23.90

自引率

1.40%

发文量

238

审稿时长

12 months

期刊介绍： Nature Chemical Biology stands as an esteemed international monthly journal, offering a prominent platform for the chemical biology community to showcase top-tier original research and commentary. Operating at the crossroads of chemistry, biology, and related disciplines, chemical biology utilizes scientific ideas and approaches to comprehend and manipulate biological systems with molecular precision. The journal embraces contributions from the growing community of chemical biologists, encompassing insights from chemists applying principles and tools to biological inquiries and biologists striving to comprehend and control molecular-level biological processes. We prioritize studies unveiling significant conceptual or practical advancements in areas where chemistry and biology intersect, emphasizing basic research, especially those reporting novel chemical or biological tools and offering profound molecular-level insights into underlying biological mechanisms. Nature Chemical Biology also welcomes manuscripts describing applied molecular studies at the chemistry-biology interface due to the broad utility of chemical biology approaches in manipulating or engineering biological systems. Irrespective of scientific focus, we actively seek submissions that creatively blend chemistry and biology, particularly those providing substantial conceptual or methodological breakthroughs with the potential to open innovative research avenues. The journal maintains a robust and impartial review process, emphasizing thorough chemical and biological characterization.