Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers(1-3), CTE has since been identified in former participants of other contact sports, ex-military personnel and following physical abuse(4-7). No disease-modifying therapies exist and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels(8,9). This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies(10,11). However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. We used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments, with resolutions down to 2.3 Å, from the brains of three individuals with CTE, one American football player and two boxers. We show that filament structures are identical in the three cases, but distinct from those of Alzheimer’s and Pick’s diseases, and from those formed in vitro(12-15). Like in Alzheimer’s disease(12,14,16-18), all six brain tau isoforms assemble into CTE filaments, and residues K274/S305-R379 form the ordered core of two identical C-shaped protofilaments. However, CTE filaments have novel protofilament interfaces, resulting in different overall morphologies. Moreover, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from Alzheimer’s disease brain. This cavity encloses an additional density that is not connected to tau, suggesting that incorporation of cofactors may play a role in tau aggregation in CTE. The tau filament structures presented here 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.