PRE-CLINICAL MODELING OF TAU EXPRESSION FOLLOWING REPEATED CLOSED HEAD IMPACT INJURY AND SIMULATED BLAST

As a result of the unanticipated observation of postmortem neuropathology in a retired, deceased professional football player, repetitive head trauma has recently received national attention. The original report suggested that repetitive head collisions, previously considered of a milder nature seemingly leaving no permanent sequelae beyond a concussion, in fact manifests itself in some athletes as chronic traumatic encephalopathy (CTE). Previously, CTE was considered a sole chronic disorder in professional boxers. The hallmark of CTE is the deposition of human microtubule associated protein tau. From pre-clinical study it is known that brain injury can induce hyperphosphorylation of tau, resulting in the disruption of its ordinary function of binding to microtubules, and the formation of neurofibrillary tangles and threads. Recent studies have expanded the observation of CTE to other contact sports and—significantly—to members of the military that sustained repeated impact-related head injuries and/or blast exposure. The purpose of this program project is to unify the research activities of three investigators’ labs to focus on the role of tauopathy following repeated milder TBI. The project design brings together expertise in axonal injury, behavioral analyses, neuroimmune function, neuroanatomical and histochemical techniques. The overall plan will derive an integrated knowledge base for establishing a connection between repetitive mild TBI, oxidative and neuroinflammatory stress, axonal damage, tau expression, and predicted ensuing behavioral impairment. The projects will each utilize the same transgenic and wild type mouse lines to cross validate and describe neuropathology by employment of three different injury models: the CNRM’s Advanced Blast Simulator (Project 1), a recently described closed head injury model that induces traumatic axonal injury (Project 2), and an in vivo cranial window model that permits the analysis of real time morphological changes immediately after brain injury (Project 3). The genetic models for the proposed program project include wild type C57Bl/6 mice and transgenic mouse lines for expression of human tau isoforms either wild type or P301S. By systematic study of injury parameters, including severity and diversity of injuries, the group will determine the mechanistic inter-relations between specific pathological features as predecessors for increased tau pathology. The combination of models will identify common and distinct manifestations observed in mice as a function of repetitive forms of milder levels of TBI from blast exposure relative to white matter traumatic axonal injury and cortical compression. This mechanistic approach will focus understanding of the pathological process of milder forms of TBI and characterize models for testable therapeutic approaches that are relevant to civilian and military head trauma.