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Repetitive mild traumatic brain injury triggers and exacerbates tau pathology and behavior

George Edwards III

University of Texas Health Science Center Houston

Background: Mild traumatic brain injury is the most common form reported in traumatic brain injury (TBI) cases and is prominent in contact sports and the military. Repetitive mild traumatic brain injury (rmTBI) can trigger the activation of several molecular cascades that lead to neuropathological consequences in the brain and has been correlated to neurodegenerative diseases such as chronic traumatic encephalopathy (CTE). CTE is a slow, progressive tauopathy that exhibits neurofibrillary tangles (NFTs) accompanied by psychiatric and cognitive manifestations. NFTs are intracellular aggregates formed from the misfolding and aggregation of tau protein. A vast majority of individuals following a TBI event demonstrate early tau accumulation suggesting a potential pathological link between TBI and tauopathies. The role of tau aggregation in brain and in subsequent clinical symptoms following rmTBI remains to be elucidated. Moreover, effective diagnostic methods for TBI and tau pathology are lacking. Our hypothesis is that rmTBI induces early formation of tau misfolded seeds that will then increase and spread leading to clinical manifestations, and these rmTBI-induced tau seeds can be used for diagnostic purposes using tau protein misfolding cyclic amplification (tau-PMCA). Methods: Naïve transgenic (Tg) tau and wild-type (WT) mice were subjected to multiple rmTBI events at early and longitudinal time-points. Animals were analyzed for behavioral changes and tau pathology following rmTBI induction. Results: rmTBI triggers tau aggregation as early as 1 hour after injury. This is a progressive event over time. Tg rmTBI mice revealed impaired learning and memory. Detection of misfolded tau in the cerebrospinal fluid of TBI-induced mice by tau-PMCA provides a promising diagnostic method to detect initial pathological changes in affected patients. Conclusion: rmTBI could be a trigger for early tau aggregation. In addition, the concomitant effect of TBI and misfolded tau may play a greater role in learning and memory impairment. Overall, this work sheds light into understanding the effect of rmTBI in relation to tau pathology subsequent to disease and will potentially provide a diagnostic tool to detect tauopathy onset and monitor TBI-induced brain damage in the future.

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