Fellowship for Bolton: Role of microglia in acute pathology of repeated concussion and CTE development

Approximately 1.7-3.8million people in the United States sustain a traumatic brain injury (TBI) every year, and 70-90% of reported cases are considered “mild”. The likelihood of repeated mild TBI is increased for individuals involved in high risk activities including military combat and many athletics. However, much remains unknown about mechanisms of damage underlying repeated concussion and how these mechanisms determine the vulnerable interval for repeated TBI. Our goal is to bridge that knowledge gap using an innovative, mechanism-oriented approach with a rodent model. Animal models of repetitive mild TBI (rmTBI) have recapitulated persistent axonal injury and microglial activation as seen with rmTBI in humans. Increasing evidence points to inflammatory responses as a mediator of not only acute pathology but also chronic neurodegeneration initiated by rmTBI. My preliminary data in a mouse model show that concussions repeated at a 24h interval result in acute microglial activation accompanied by localized axonal injury and neurodegeneration. My overarching goal is to highlight the mechanisms underlying the pathology of repeated concussion, in order to elucidate potential therapeutic interventions. In Aim 1, I will use two experimental approaches to manipulate posttraumatic microglial activation to determine the causative role of microglia in the neuropathology of rmTBI. First, progranulin-deficient (GRN KO) mice, which exhibit a greatly exacerbated microglial response after penetrating brain injury, will be used to amplify microglial reactivity after rmTBI. Second, treatment with ibuprofen, a widely used anti-inflammatory drug, will be used to attenuate microglial reactivity after rmTBI. In Aim 2, I will examine long-term consequences of rmTBI, again utilizing GRN KO mice as a tool to facilitate early onset of neurodegenerative changes triggered by concussion. In the absence of any CNS insult, GRN KO mice show age-related increases in microglial activation, which precede late onset (12-18mo) accumulation of phosphorylated TAR DNA binding protein-43 (pTDP43) and deficits in learning and memory (18mo). pTDP43 accumulation is a signature pathology in Chronic Traumatic Encephalopathy (CTE), a neurodegenerative disease triggered by repeated concussions. CTE is associated with memory impairment, anxiety, motor deficits, and chronic activation of microglia but is only definitively diagnosed post-mortem by the accumulation of hyper-phosphorylated tau (pTau) and pTDP43 in the brain. Despite efforts of multiple laboratories no rodent model of rmTBI has yet recapitulated the full spectrum of CTE-related neuropathology. I postulate that GRN deficiency will serve as an catalyst to accelerate the onset of CTE-like changes in mice. My overall hypothesis is that repeated concussions induce persistent microgliosis, accelerating the onset of CTE-like behavioral and histopathological consequences.