Cryo-EM structures of tau filaments from Alzheimer's disease

Anthony W.P. Fitzpatrick, Benjamin Falcon, Shaoda He, Alexey G. Murzin, Garib Murshudov, Holly Garringer, R. Anthony Crowther, Bernardino Ghetti, Michel Goedert, Sjors H.W. Scheres

Research output: Contribution to journalArticle

248 Citations (Scopus)

Abstract

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)185-190
Number of pages6
JournalNature
Volume547
Issue number7662
DOIs
StatePublished - Jul 13 2017

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Neurodegenerative Diseases
Cryoelectron Microscopy
Alzheimer Disease
tau Proteins
Amyloid Plaques
Amyloid
Cerebral Cortex
Seeds
Brain
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H., ... Scheres, S. H. W. (2017). Cryo-EM structures of tau filaments from Alzheimer's disease. Nature, 547(7662), 185-190. https://doi.org/10.1038/nature23002

Cryo-EM structures of tau filaments from Alzheimer's disease. / Fitzpatrick, Anthony W.P.; Falcon, Benjamin; He, Shaoda; Murzin, Alexey G.; Murshudov, Garib; Garringer, Holly; Crowther, R. Anthony; Ghetti, Bernardino; Goedert, Michel; Scheres, Sjors H.W.

In: Nature, Vol. 547, No. 7662, 13.07.2017, p. 185-190.

Research output: Contribution to journalArticle

Fitzpatrick, AWP, Falcon, B, He, S, Murzin, AG, Murshudov, G, Garringer, H, Crowther, RA, Ghetti, B, Goedert, M & Scheres, SHW 2017, 'Cryo-EM structures of tau filaments from Alzheimer's disease', Nature, vol. 547, no. 7662, pp. 185-190. https://doi.org/10.1038/nature23002
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer H et al. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. https://doi.org/10.1038/nature23002
Fitzpatrick, Anthony W.P. ; Falcon, Benjamin ; He, Shaoda ; Murzin, Alexey G. ; Murshudov, Garib ; Garringer, Holly ; Crowther, R. Anthony ; Ghetti, Bernardino ; Goedert, Michel ; Scheres, Sjors H.W. / Cryo-EM structures of tau filaments from Alzheimer's disease. In: Nature. 2017 ; Vol. 547, No. 7662. pp. 185-190.
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