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Open Access 01-11-2018 | Original Paper

Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold

Authors: Benjamin Falcon, Wenjuan Zhang, Manuel Schweighauser, Alexey G. Murzin, Ruben Vidal, Holly J. Garringer, Bernardino Ghetti, Sjors H. W. Scheres, Michel Goedert

Published in: Acta Neuropathologica | Issue 5/2018

Abstract

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer’s disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies.

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Title: Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold
Authors: Benjamin Falcon
Wenjuan Zhang
Manuel Schweighauser
Alexey G. Murzin
Ruben Vidal
Holly J. Garringer
Bernardino Ghetti
Sjors H. W. Scheres
Michel Goedert
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 5/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1914-z

At a glance: The STEP trials

Springer Medicine

Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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