英国利兹大学René A. W. Frank团队近期取得重要工作进展，他们研究通过冷冻电子断层扫描(CryoET)，鉴定分析了死后阿尔茨海默病大脑中β淀粉样蛋白和tau蛋白在的结构。相关研究成果2024年7月10日在线发表于《自然》杂志上。

据介绍，大多数神经退行性疾病的一个决定性病理特征是蛋白质组装成淀粉样蛋白，形成疾病特异性结构。在阿尔茨海默病中，其特征是具有疾病特异性构象的β-淀粉样蛋白和tau蛋白的沉积。人脑中淀粉样蛋白的原位结构尚不清楚。

研究人员使用冷冻电镜、靶向冷冻切片、冷冻聚焦离子束扫描电镜和冷冻电子断层扫描，确定了死后阿尔茨海默病供体脑中β-淀粉样蛋白和tau蛋白的组织结构。β-淀粉样蛋白斑块由原纤维(其中一些是分枝的)和原丝(平行排列和晶格状结构)组成。细胞外小泡和立方颗粒定义了β-淀粉样蛋白斑块的非淀粉样成分。

相比之下，tau内含物形成了平行的无分支细丝团。对单张断层扫描图中的136条tau细丝群进行亚断层扫描，可发现组织内成对螺旋细丝的多肽骨架构象和细丝极性取向。大多数簇内的细丝彼此相似，但不同簇之间的细丝不同，这表明淀粉样蛋白的异质性是按亚细胞位置进行空间组织的。

总之，这一研究概述的人类供体组织的原位结构方法可应用于广泛的神经退行性疾病。

附：英文原文

Title: CryoET of β-amyloid and tau within postmortem Alzheimer’s disease brain

Author: Gilbert, Madeleine A. G., Fatima, Nayab, Jenkins, Joshua, OSullivan, Thomas J., Schertel, Andreas, Halfon, Yehuda, Wilkinson, Martin, Morrema, Tjado H. J., Geibel, Mirjam, Read, Randy J., Ranson, Neil A., Radford, Sheena E., Hoozemans, Jeroen J. M., Frank, Ren A. W.

Issue&Volume: 2024-07-10

Abstract: A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures1. In Alzheimer’s disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles and cuboidal particles defined the non-amyloid constituents of β-amyloid plaques. By contrast, tau inclusions formed parallel clusters of unbranched filaments. Subtomogram averaging a cluster of 136 tau filaments in a single tomogram revealed the polypeptide backbone conformation and filament polarity orientation of paired helical filaments within tissue. Filaments within most clusters were similar to each other, but were different between clusters, showing amyloid heterogeneity that is spatially organized by subcellular location. The in situ structural approaches outlined here for human donor tissues have applications to a broad range of neurodegenerative diseases.

DOI: 10.1038/s41586-024-07680-x

Source: https://www.nature.com/articles/s41586-024-07680-x