cis p-tau: early driver of brain injury and tauopathy blocked by antibody

Traumatic brain injury (TBI), characterized by acute neurological dysfunction, is one of the best known environmental risk factors for chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD), whose defining pathologic features include tauopathy made of phosphorylated tau (p-tau). However, tauopathy has not been detected in early stages after TBI and how TBI leads to tauopathy is unknown. Here we find robust cis p-tau pathology after sportand military-related TBI in humans and mice. Acutely after TBI in mice and stress in vitro, neurons prominently produce cis p-tau, which disrupts axonal microtubule network and mitochondrial transport, spreads to other neurons, and leads to apoptosis. This process, termed “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 after TBI and leads to tauopathy in CTE and AD, and cis antibody may be further developed to detect and treat TBI, and prevent progressive neurodegeneration after injury. Traumatic brain injury (TBI) is the leading cause of death and disability in children and young adults1 and in the US, ~2.5 million people suffer TBI each year2. Nearly 20% of the 2.3 million troops deployed by the military have sustained TBI3. Repetitive mild TBI (rmTBI), seen in contact sports, or even single moderate/severe TBI (ssTBI), seen in military blasts, may cause acute and potentially long-lasting neurological dysfunction, including the development of chronic traumatic encephalopathy (CTE)4-9. TBI is also an established environmental risk factor for Alzheimer's disease (AD)7-12. However, no treatment is available to prevent CTE or AD. CTE is characterized by neurofibrillary tangles made of hyperphosphorylated tau4-9. Such tangles are also a hallmark of AD and related neurodegenerative disorders, collectively termed tauopathies13, 14. Tauopathy spreads in brains15-19 and is reduced by immunotherapy against tauopathy epitopes20-22. However, since little tauopathy is detectable acutely or subacutely after TBI in humans and mice5, 7-9, 23-25, whether tauopathy is a cause or consequence of post-traumatic neurodegeneration is unknown. We have identified a unique proline isomerase, Pin1 that inhibits tauopathy in AD by converting the phosphorylated Thr231-Pro motif in tau (p-tau) from cis to trans in AD cell and mouse models26-34. In human AD, Pin1 is inhibited by multiple mechanisms27, 29, 35-37, whereas the Pin1 genetic polymorphism that prevents its down-regulation is associated with delaying AD age of onset38. In addition, Pin1 is located at a locus associated with late-onset AD39, p-tau appears early in pretangle AD neurons40 and its cerebrospinal fluid level correlates with memory loss in MCI and AD41. We have developed antibodies that Kondo et al. Page 2 Nature. Author manuscript; available in PMC 2016 January 23. A uhor M anscript