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

Nature volume 547, pages 185190 (13 July 2017) | Download Citation

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.

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Acknowledgements

These findings mark the culmination of a conversation at the MRC Laboratory of Molecular Biology 34 years ago between A. Klug, the late M. Roth and R.A.C. about the structural analysis of Alzheimer filaments. We thank the patient’s family for donating brain tissue; M. R. Farlow for clinical evaluation; F. Epperson, R. M. Richardson and U. Kuederli for human brain collection and analysis; P. Davies, M. Hasegawa and M. Novak for antibodies MC-1, TauC4 and MN423, respectively; H. Zhou for use of the Titan Krios at UCLA EICN; S. Chen, C. Savva and G. Cannone for support with electron microscopy at the MRC Laboratory of Molecular Biology; T. Darling and J. Grimmett for help with computing; and M. Skehel for support with mass spectrometry. M.G. is an Honorary Professor in the Department of Clinical Neurosciences of the University of Cambridge. This work was supported by the UK Medical Research Council (MC_UP_A025_1012 to G.M., MC_U105184291 to M.G. and MC_UP_A025_1013 to S.H.W.S.), the European Union (Marie Curie International Outgoing Fellowship to A.W.P.F., Joint Programme-Neurodegeneration Research to M.G. and B.F., and Horizon 2020 IMPRiND to M.G. and A.W.P.F.), the US National Institutes of Health (grant P30-AG010133 to B.G.) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (to B.G.).

Author information

Author notes

    • Michel Goedert
    •  & Sjors H. W. Scheres

    These authors jointly supervised this work.

Affiliations

  1. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK

    • Anthony W. P. Fitzpatrick
    • , Benjamin Falcon
    • , Shaoda He
    • , Alexey G. Murzin
    • , Garib Murshudov
    • , R. Anthony Crowther
    • , Michel Goedert
    •  & Sjors H. W. Scheres
  2. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

    • Holly J. Garringer
    •  & Bernardino Ghetti

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Contributions

B.G. performed neuropathology; H.J.G. performed genetic analysis; B.F. conducted filament extraction and immunolabelling; A.W.P.F. performed cryo-EM; S.H. and S.H.W.S. provided cryo-EM software; A.W.P.F. and S.H.W.S. analysed cryo-EM data; A.W.P.F., A.G.M. and G.M. built the atomic model; R.A.C. contributed to the inception of the study; M.G. and S.H.W.S. supervised the project; all authors contributed to writing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michel Goedert or Sjors H. W. Scheres.

Reviewer Information Nature thanks E. Egelman, D. Eisenberg and B. Meier for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature23002

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