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

Nature volume 547, pages 185–190 (2017)Cite this article

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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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Figure 1: Structure of tau filaments from Alzheimer's brain.
Figure 2: Cross-sections of the PHF and SF cryo-EM structures.
Figure 3: The common protofilament core.
Figure 4: Protofilament interface in PHFs and SFs.
Figure 5: Schematic representation of full-length tau filaments.

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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.).

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Author notes

  1. Michel Goedert and Sjors H. W. Scheres: These authors jointly supervised this work.

Authors and 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, 46202, Indiana, 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.

Corresponding authors

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

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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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Extended data figures and tables

Extended Data Figure 1 Immunolabelling of the brain sample.

a, b, Immunolabelling of the sarkosyl-insoluble fraction from the patient’s temporal cortex. a, Immunoblots using anti-tau antibodies BR133 (N terminus), BR135 (R3), TauC4 (R4), BR134 (C terminus), AT8 (pS202/pT205) and MC-1. b, Immunogold negative-stain electron microscopy of PHFs and SFs with BR133, BR135, TauC4, BR134, AT8 and MC-1. Scale bar, 500 Å. c, Light microscopy of sections from the temporal cortex showing staining of neurofibrillary tangles, neuropil threads and plaque neurites using RD3 (3R), anti-4R (4R), AT8 and AT100 (pT212/pS214/pT217). Nuclei are counterstained blue. Scale bar, 50 μm.

Extended Data Figure 2 PHFs and SFs at various stages during purification.

a–c, Cryo-EM micrographs and reference-free 2D class averages for PHFs (blue insets) and SFs (green insets) for the tau sample after the sucrose step (a), gel filtration (b), and pronase treatment (c). Examples of PHFs and SFs in the micrographs are indicated with blue and green arrowheads, respectively. Scale bars, 500 Å. d, Western blots with antibody HT7 (Thermo; catalogue nr. MN1000) of the total lysate, sarkosyl-soluble and sarkosyl-insoluble fractions of HEK 293T cells expressing wild-type 0N4R human tau and treated with (+) or without (−) the sarkosyl-insoluble fraction from the patient’s temporal cortex following gel filtration show that the cryo-EM sample is capable of seeding aggregation of human tau. e, Densitometric analysis (mean ± s.e.m., n = 3) of HT7 blots of sarkosyl-insoluble fractions from cells.

Extended Data Figure 3 Cryo-EM map and model comparisons.

a, Fourier shell correlation (FSC) curves between two independently refined half-maps for the full-length (FL) PHFs (blue, solid); FL SFs (green, solid); pronase-treated (PT) PHFs (blue, dashed) and PT SFs (green, dashed). b, FSC curves between the cryo-EM reconstructions and the refined atomic models, using the same colour coding as in a. c, Local resolution estimates for the four cryo-EM reconstructions. d, Comparison of power spectra (the squared amplitudes of the Fourier transform, FT) of reference-free 2D class averages with those of corresponding projections of the atomic models. In PHFs the approximate 21 screw symmetry between subunits on the two protofilaments leads to off-meridional n = 1 Bessel function peaks on the 1/(4.7 Å) layer line (blue arrows). For SFs, in which the asymmetric unit consists of two subunits at the same level, one from each protofilament, there is a meridional n = 0 Bessel function peak on the 1/(4.7 Å) layer line (green arrows).

Extended Data Figure 4 Close-up views of cryo-EM map and models.

The R3–R4 model provides the best fit to cryo-EM densities in the β-helix region (top row) and the cross-β region near the termini (second row) of the PHF protofilaments. The same model also provides the best fit to densities at the cross-β regions near the termini of the two protofilaments (third and fourth row) in SFs. Major discrepancies between the cryo-EM density and alternative atomic models (consisting of R2–R3, R1–R3 and R1–R2 cores) are highlighted with red dashed outlines.

Extended Data Figure 5 Comparison of PHF and SF protofilament cores.

a, The PHF backbone atoms are shown in blue and the SF backbone atoms in green. The r.m.s.d. between the backbone atoms is 1.2 Å. b, As in a, but showing all atoms.

Extended Data Figure 6 Cross-sections of the pronase-treated PHF and SF cryo-EM structures.

Sharpened maps are shown in blue for PHFs (a) and green for SFs (b). Additional densities in contact with lysines 317 and 321 are indicated with red arrows. Unsharpened density, lowpass filtered to 4.5 Å resolution for the PHFs, is shown in grey. The unsharpened density that is highlighted with an orange background is reminiscent of a less ordered β-sheet and could accommodate an additional 16 amino acids, which would correspond to a mixture of residues 259–274 (R1) from 3R tau and residues 290–305 (R2) from 4R tau.

Extended Data Figure 7 Mass-spectrometry and antibody labelling support the model of an R3–R4 core.

a, Relative abundance of identified peptides from the pronase-treated filaments by mass spectrometry (shown in green). The peptide used to produce anti-4R tau is shown in blue (with a D instead of an N at position 279). The epitope of MN423 is shown in orange. b, Immunogold negative-stain electron microscopy of PHFs and SFs with anti-4R tau (top) and MN423 (bottom) with (+) and without (−) pronase treatment. Scale bar, 100 nm.

Extended Data Figure 8 Comparison of the tau β-helix with the HET-s β-helices.

a, Overlay of the backbones of the β-helix in tau (cyan) and the HET-s β-helices (orange and purple). The r.m.s.d. between the backbone atoms is 1.3 Å. b, c, All-atom overlays of the tau and HET-s β-helices.

Extended Data Figure 9 Hypothetical core structures.

Schematic views of hypothetical core structures of R1–R3 from 3R tau (a), R2–R3 from 4R tau (b) and R1–R2 from 4R tau (c). Note that in these conformations, the β-helices would only be 18 instead of 19 residues long, because of an additional residue (D348) in R4. Still, the β-helices would have mainly hydrophobic residues in the core, polar residues on the outside, and the pivotal glycine closing the motif. Each hypothetical core structure also contains the first 10 amino acids of the next repeat (R4 for R1–3 and R2–R3; R3 for R1–R2). It could also be that there are cores made of three or more repeats.

Extended Data Table 1 Cryo-EM structure determination and model statistics for full-length (FL) and pronase-treated (PT) filaments
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Fitzpatrick, A., Falcon, B., He, S. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017). https://doi.org/10.1038/nature23002

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