Role of tau in induction of CTE after repeated concussive TBI

Chronic traumatic encephalopathy (CTE) is a progressive brain disorder caused by repetitive concussive head injuries. Mechanisms underlying the development of this disease are currently unknown and no treatments are available. CTE is characterized pathologically by the cortical foci of hyperphosphorylated, aggregated tau protein, neuroinflammation, myelinated axonopathy and progressive neurodegeneration. Clinically, CTE is characterized by irritability, distractibility, memory disturbances and decline in executive function. Although repetitive mild head injury can result in CTE in humans, rodent models of repeated concussion have not yet successfully recapitulated the spectrum of CTE pathology. An effective animal model is urgently needed in order to manipulate the system, identify risk factors, and test therapeutic interventions. We hypothesize that the severity of CTE-related neurodegeneration and behavioral dysfunction following repeated concussions is proportional to the extent of aberrant tau accumulation in the brain. We will test this hypothesis in Aim 1 using a transgenic mouse (rTg4510) expressing human tau with a pathogenic mutation that exhibits age-dependent accumulation of abnormally phosphorylated tau. We postulate that overexpression of tau will accelerate posttraumatic phospho-tau accumulation, precipitating an earlier onset of neurodegeneration and cognitive decline after repeated concussion. rTg4510 and littermate control mice will receive two mild impacts to the skull or sham impacts at a 24h interval. The progression of CTE-like pathology will be evaluated over a period of days to months utilizing a comprehensive battery of tests including markers of tau pathology, neurodegeneration, cognitive impairment, and anxiety- and depression-like symptoms to evaluate the full spectrum of CTE pathology as a function of tau overexpression. In Aim 2, we will test our overall hypothesis using methylene blue, a therapeutic intervention aimed at abrogating aggregation of hyperphosphorylated tau. We postulate that methylene blue administration will attenuate chronic neurodegeneration and behavioral impairment. Both preventative and treatment paradigms will be tested. Hence, rTg4510 and wildtype littermate mice will receive methylene blue or placebo beginning either the day of or two weeks after the second concussion. In all cases, two months after injury we will (1) confirm hyperphosphorylated tau as a therapeutic target, (2) provide the first proof-of-principle demonstration of the efficacy of methylene blue in treating trauma-induced tau neuropathology, and (3) establish that early methylene blue treatment is effective in slowing the onset of CTE-like pathology. These studies will establish a novel model relevant for the study of CTE, provide new insights into the cellular mediators of chronic neurodegeneration and neurological decline after repeated concussion, and yield the first preclinical data on methylene blue treatment in a model of TBI.