Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy and Alzheimer’s disease, the defining pathologic features of which include tauopathy made of phosphorylated tau protein (P-tau). However, tauopathy has not been detected in the early stages after TBI, and how TBI leads to tauopathy is unknown. Here we find robust cis P-tau pathology after TBI in humans and mice. After TBI in mice and stress in vitro, neurons acutely produce cis P-tau, which disrupts axonal microtubule networks and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, which we term ‘cistauosis’, appears long before other tauopathy. Treating TBI mice with cis antibody blocks cistauosis, prevents tauopathy development and spread, and restores many TBI-related structural and functional sequelae. Thus, cis P-tau is a major early driver of disease after TBI and leads to tauopathy in chronic traumatic encephalopathy and Alzheimer’s disease. The cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. Here the cis form of tau protein, which disrupts axonal microtubules and transport, spreads to other neurons, and leads to apoptosis in vitro and in vivo, is found to be produced by neurons immediately after traumatic brain injury (TBI); treating TBI mice with cis antibody blocks early production of cis tau, prevents tauopathy and spread and restores brain structural and functional outcomes, and may be further developed to treat TBI and to prevent neurodegeneration after injury. The symptoms of traumatic brain injury (TBI), a common condition in players of contact sports and in the military, are associated with acute neurological dysfunction and TBI is a major risk factor for Alzheimer's disease. Tauopathy associated with the aggregation of phosphorylated tau protein (P-tau) in the brain is a defining feature of the neurodegeneration associated with chronic traumatic encephalopathy and Alzheimer's but it has not been observed in the early stages of TBI. Here Kun Ping Lu and colleagues show that tauopathy caused by cis P-tau, but not trans P-tau, is an early driver of brain injury in patients with TBI and in mouse models. Treating TBI mice with cis antibody blocks early production of cis P-tau and prevents further tauopathy and spread, and may be further developed to treat TBI after injury.