Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1,2,3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4,5,6,7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro12,13,14,15. Similar to Alzheimer’s disease12,14,16,17,18, all six brain tau isoforms assemble into filaments in CTE, and residues K274–R379 of three-repeat tau and S305–R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer’s disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer’s disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.
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Cryo-EM maps for case 1 have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-0527 for CTE type I tau filament and EMD-0528 for CTE type II tau filament. Refined atomic models for case 1 have been deposited in the PDB under accession numbers 6NWP for CTE type I tau filament and 6NWQ for CTE type II tau filament. Whole-exome and whole-genome sequencing, and C9orf72 hexanucleotide repeat expansion results, have been deposited in the National Institute on Ageing Alzheimer’s Disease Data Storage Site (NIAGADS), under accession number NG00077. Any other relevant data are available from the corresponding authors upon reasonable request.
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We thank the patients’ families for donating brain tissue; J. Gonzalez, P. Dooley, F. Epperson, R. M. Richardson, M. Danley and U. Kuederli for brain collection and technical support with neuropathology; M. Hasegawa for antibody TauC4; G. Cannone, C. Savva, Z. Yang and C. Wigger for support with electron microscopy; T. Nakane for help with RELION; G. Murshudov for help with REFMAC; T. Darling and J. Grimmett for help with high-performance computing. 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_1013 to S.H.W.S. and MC_U105184291 to M.G.), the European Union (Joint Programme-Neurodegeneration Research REfrAME to B.F. and M.G. and the EU/EFPIA/Innovative Medicines Initiative  Joint Undertaking IMPRiND, project 116060, to M.G.), the US National Institutes of Health (P30AG010133 and U01NS110437), the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine to B.G. and R.V., and the Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine to K.L.N. Some of the tissue specimens were obtained with support of the Massachusetts Alzheimer’s Disease Research Center (P50 AG005134). This study was supported by the MRC-LMB EM facility. We acknowledge DIAMOND for access to and support of the cryo-EM facilities at the UK electron Bio-Imaging Centre (eBIC), proposal EM17434, funded by the Wellcome Trust, the MRC and the BBSRC, for acquisition of the case 1 cryo-EM dataset; the Midlands Regional Cryo-EM facility at the Leicester Institute of Structural and Chemical Biology (LISCB), major funder MRC, for acquisition of the case 3 cryo-EM dataset; and the Center for Medical Genomics of Indiana University School of Medicine for next-generation sequencing.
Nature thanks Edward H. Egelman and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Coexisting pathologies. a, Staining of tau inclusions in the temporal cortex of CTE cases 1, 2 and 3 using antibodies RD3 (three-repeat tau), anti-4R (four-repeat tau) and AT8 (pS202 and pT205 tau). Scale bar, 50 μm. b, Gallyas–Braak silver staining of tau inclusions in the temporal cortex of CTE cases 2 and 3. Scale bar, 50 μm. c, Staining of tau inclusions in the spinal cord of CTE cases 1 and 2 using antibody AT8. Scale bar, 50 μm. d, Immunoblots of sarkosyl-insoluble tau from the temporal cortices of CTE cases 1, 2 and 3 using antibodies BR133, BR134 and AT8. e, Staining of a TDP-43 inclusion in the spinal cord of CTE case 1. Scale bar, 25 μm. f, Staining of CTE case 2 for poly-GA inclusions in the cerebellum and TDP-43 inclusions in the spinal cord, temporal cortex, hippocampus and amygdala. Top right, double-labelling of tau inclusions (AT8, brown) and TDP-43 inclusions (red) is shown. Scale bars, 25 μm (top), 50 μm (bottom). g, Staining of CTE case 3 for α-synuclein inclusions in the substantia nigra, dorsal motor nucleus (DMN) of the vagus nerve and locus coeruleus. Scale bar, 50 μm. Nuclei were counterstained blue in all images.
a, b, Immunoblots and immunolabelling of tau filaments extracted from the temporal cortices of CTE cases 1, 2 and 3. a, Immunoblots of sarkosyl-insoluble tau using antibodies BR136, anti-4R, BR135 and TauC4. b, Representative immuno-EM images of tau filaments labelled with antibodies BR136 and anti-4R. Unlike BR136 and anti-4R, antibodies BR135 and TauC4 did not label the filaments, which indicates that their epitopes lie within the ordered filament cores. Scale bar, 200 nm.
a, Two-dimensional class averages spanning an entire helical crossover of type I and type II tau filaments from CTE cases 1–3. b, Cryo-EM structure of paired helical filaments from the temporal cortex of CTE case 1.
a, b, Fourier shell correlation curves between two independently refined half-maps (bold black line); between the final cryo-EM reconstruction and refined atomic model (bold red line); between the first half-map and the atomic model refined against the first half-map (brown line); and between the second half-map and the atomic model refined against the first half-map (blue dashed line) for CTE type I (a) and CTE type II (b) filaments. c, d, Local resolution estimates for the CTE type I (c) and CTE type II (d) filament reconstructions. e, f, Views normal to the helical axis of the CTE type I (e) and CTE type II (f) filament reconstructions.
a–c, Close-up view of the cryo-EM map with the atomic model overlaid, showing densities for oxygens atoms of the peptide groups (a) and ordered solvent molecules (b). c, Side-chain conformations for the alternating positively and negatively charged solvent-exposed side chains of residues 336–343 in successive rungs.
a, Schematic of the CTE tau filament fold. b, Rendered view of the secondary structure elements in the CTE fold, depicted as three successive rungs. c, As in b, but in a view perpendicular to the helical axis, revealing the changes in height within a single molecule.
Extended Data Fig. 7 Comparison of CTE type I and CTE type II tau filament folds and protofilament interfaces.
a, The CTE type I protofilament structure is shown in purple and the CTE type II protofilament structure is shown in gold. b, As in a, but showing backbone atoms only. c, d, Packing between residues 322CGSLGNIH329 of the two protofilaments in CTE type I filaments (c) and between residues 331KPGGGQVE338 of the two protofilaments in CTE type II filaments (d).
Threefold astigmatism (antisymmetrical; top) and fourfold astigmatism (symmetrical; bottom) measured in per-Fourier-pixel average phase-error plots (left) and represented by our parametric model (right) for CTE type I tau filaments from case 1. The plot shows image frequencies up to 2.9 Å. The outlier ring at 4.7 Å corresponds to the dominant frequency given by a double-repetition of the helix. This ring has been excluded from the parametric fit.
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Falcon, B., Zivanov, J., Zhang, W. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019). https://doi.org/10.1038/s41586-019-1026-5
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