Project Summary Epidemiological studies have revealed traumatic brain injury (TBI) as an important risk factor for development of Alzheimer’s disease (AD), a progressive neurodegenerative disease which results in dementia and ultimately, death. The mechanistic links between the two conditions are not well understood. Furthermore, there are no widely effective FDA approved treatments for cognitive impairment, exposing an existing large unmet medical need. Not only are major mechanisms of secondary injury—oxidative stress and neuroinflammation—thought to contribute to neurodegeneration after TBI, but are key components of pathology found in AD brains as well. The literature also suggests that TBI induces tau hyperphosphorylation and aggregation of amyloid-, neurotoxic entities thought to initiate and propagate AD. What has been missing is an underlying link between these processes. Preliminary data from our lab indicate that adenosinergic dysregulation occurs after TBI in wild type mice, resulting from altered expression of ectonucleotidase and adenosine kinase (ADK) which are key regulators of adenosinergic tone. Adenosinergic axis targeting has been tested experimentally for cognitive impairment after TBI and in transgenic AD mice, but receptor specificity and cardiovascular side effects have prevented these approaches from becoming viable treatments in humans. Our preliminary data provide evidence that targeting the adenosine subtype 3 receptor (A3AR) with >10,000 fold receptor specificity prevents cognitive impairment after TBI in wild type mice and reverses it in an accelerated aging model of AD without noticeable side effects. I propose that TBI induces rapid adenosinergic dysregulation that accelerates pathological changes which lead to AD, and that supplementing adenosine signaling at the A3AR prevents the acceleration and subsequent cognitive impairment. Aim 1 of my proposal will test the hypothesis that TBI accelerates the progression of the AD phenotype in a non-transgenic mouse model of AD by inducing TBI in young, unimpaired mice and timing the onset to cognitive impairment compared to that in uninjured mice. Aim 2 will test the hypothesis that targeting the A3AR with a highly specific agonist is sufficient to prevent acceleration and cognitive impairment by inducing TBI in mice and treating with a specific A3AR agonist or its vehicle. Tissues will be analyzed biochemically and histologically in both Aims. A3AR agonists are currently in clinical trials as anti-cancer and anti-inflammatory agents. The successful completion of the proposed studies could add another clinical indication for A3AR agonists, providing a break-through in the treatment of cognitive impairment for both TBI and AD patients. This project has been carefully considered and integrated into a comprehensive fellowship training plan which includes state of the art technical training, diverse mentorship, scientific and clinical career development duties, and ample oppor...