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 opportunities to present my findings. All the essential resources required for
completion of the project and fellowship training are abundant in Saint Louis University’s environment.
