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

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Alzheimer Disease
Gold
Electron Microscopy
Coloring Agents
Frontal Lobe
Cryoelectron Microscopy
tau Proteins
Terminal Repeat Sequences
Brain
Neurodegenerative Diseases
Atrophy
Amino Acids
Alzheimer disease type 2

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. / Falcon, Benjamin; Zhang, Wenjuan; Schweighauser, Manuel; Murzin, Alexey G.; Vidal, Ruben; Garringer, Holly; Ghetti, Bernardino; Scheres, Sjors H.W.; Goedert, Michel.

In: Acta Neuropathologica, 01.01.2018.

Research output: Contribution to journalArticle

Falcon, Benjamin ; Zhang, Wenjuan ; Schweighauser, Manuel ; Murzin, Alexey G. ; Vidal, Ruben ; Garringer, Holly ; Ghetti, Bernardino ; Scheres, Sjors H.W. ; Goedert, Michel. / Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. In: Acta Neuropathologica. 2018.
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