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

DOI: 10.1007/s00401-018-1914-z DOI Help

Authors: Benjamin Falcon (MRC Laboratory of Molecular Biology) , Wenjuan Zhang (MRC Laboratory of Molecular Biology) , Manuel Schweighauser (MRC Laboratory of Molecular Biology) , Alexey G. Murzin (MRC Laboratory of Molecular Biology) , Ruben Vidal (Indiana University School of Medicine) , Holly J. Garringer (Indiana University School of Medicine) , Bernardino Ghetti (Indiana University School of Medicine) , Sjors H. W. Scheres (MRC Laboratory of Molecular Biology) , Michel Goedert (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acta Neuropathologica , VOL 136 , PAGES 699 - 708

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 17434

Open Access Open Access

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.

Journal Keywords: Alzheimer’s disease; Neurodegenerative diseases; Tau protein; Paired helical filaments; Straight filaments; Electron cryo-microscopy; Immuno-gold negative-stain electron microscopy

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

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