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

Madeleine A. G. Gilbert, Nayab Fatima, Joshua Jenkins, Thomas J. O’Sullivan, Andreas Schertel, Yehuda Halfon, Martin Wilkinson, Tjado H. J. Morrema, Mirjam Geibel, Randy J. Read, Neil A. Ranson, Sheena E. Radford, Jeroen J. M. Hoozemans and René A. W. Frank ()
Additional contact information
Madeleine A. G. Gilbert: University of Leeds
Nayab Fatima: University of Leeds
Joshua Jenkins: University of Leeds
Thomas J. O’Sullivan: University of Leeds
Andreas Schertel: Carl Zeiss Microscopy GmbH
Yehuda Halfon: University of Leeds
Martin Wilkinson: University of Leeds
Tjado H. J. Morrema: Amsterdam University Medical Centers
Mirjam Geibel: Carl Zeiss Microscopy GmbH
Randy J. Read: University of Cambridge
Neil A. Ranson: University of Leeds
Sheena E. Radford: University of Leeds
Jeroen J. M. Hoozemans: University of Leeds
René A. W. Frank: University of Leeds

Nature, 2024, vol. 631, issue 8022, 913-919

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07680-x Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:631:y:2024:i:8022:d:10.1038_s41586-024-07680-x

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07680-x

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().