CryoET of β-amyloid and tau within postmortem Alzheimer's disease brain
成果类型：
Article
署名作者：
Gilbert, Madeleine A. G.; Fatima, Nayab; Jenkins, Joshua; O'Sullivan, 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, Rene A. W.
署名单位：
University of Leeds; University of Leeds; Carl Zeiss AG; University of Leeds; University of Amsterdam; University of Cambridge
刊物名称：
Nature
ISSN/ISSBN：
0028-4266
DOI：
10.1038/s41586-024-07680-x
发表日期：
2024-07-25
页码：
913-+
关键词：
paired helical filaments
neurodegenerative diseases
electron-microscopy
em
Visualization
tomography
fluorescence
pathology
proteins
plaques
摘要：
A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures(1). In Alzheimer's disease, this is characterized by the deposition of beta-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 beta-amyloid and tau pathology in a postmortem Alzheimer's disease donor brain. beta-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 beta-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.