This project seeks to examine a treatment for chronic traumatic encephalopathy (CTE). CTE is a degenerative disease that afflicts individuals who have received multiple concussive injuries such as soldiers or players of professional contact sports. It is often marked by progressive neurological deterioration. The disease may lead to memory loss, mood problems, suicidality and dementia and there is presently no known cure. Neuropathologically the disease is associated with chronic neuroinflammation, axonal injury, brain atrophy and tauopathy. There is extensive evidence that long term inflammation worsens neurodegenerative diseases, and specifically tauopathies. This study examines the hypothesis that downregulating this inflammation will slow or arrest the progression of CTE. The proposal employs JM4, a novel immune/inflammatory regulatory agent, to control neuroinflammation. JM4 is a short peptide derived from the cytokine erythropoietin. Whole molecule erythropoietin has well established neuroprotective and immune/inflammatory modulating effects. However, its use in clinical settings is limited since it can lead to dangerous polycythemic levels of red blood cells. JM4 is a short peptide fragment of erythropoietin that retains the cytokine's beneficial effects without the side effect of hematopoiesis. Preliminary studies show that it is highly effective in reducing the immune inflammatory responses in several models of experimental autoimmune encephalomyelitis. Furthermore, in a mouse model of Alzheimer's disease it reduces clinical signs, microglial and astrocytic activation and tauopathy. Preliminary data in a mouse model of CTE indicates that it decreases the associated memory and anxiety deficits. The proposed studies will examine the ability of JM4 to treat CTE using the following experiments: 1) Establishing a model of CTE. Since there is presently no generally accepted animal model of CTE we will appraise two closed cranium models that have been reported in the literature. The first employs multiple direct impacts to the head of experimental mice over a 1 week period. The second model exposes the mice to blast like loading by placing them in the path of a simulated explosion. Both models have been reported to produce chronic neuroinflammation, tauopathy and behavioral deficits. Mice will be followed using tests of anxiety, memory and motor ability. After 6 months, mice will be sacrificed to study neuroinflammation, proinflammatory cytokines and tauopathy using immunohistochemistry. 2) Examining the effect of JM4 in the treatment of CTE. The optimum model from experiment 1 will be selected and the efficacy of JM4 will be tested. Mice will be exposed to the selected injury and then treated with JM4 for 10 consecutive days, either immediately following the injury, or after a 1 month delay (to simulate the effect of delaying treatment until behavioral deficits become apparent). Mice will be examined using the same behavioral and immunohistochemical tests employed above. We anticipate that treatment of the mice with JM4 will reduce inflammation and decrease or eliminate both the behavioral and neuropathological signs of CTE. If successful this will be the first potential treatment developed for this disease.

Public Health Relevance

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease afflicting individuals who have received multiple mild concussions. It appears to be present in a large percentage of professional players of contact sports, and has been repeatedly found in studies of military veterans. The disease can have devastating effects including memory and emotional problems, suicidality and dementia. The disease typically progresses over a period of years or decades, and there is currently no known treatment that can slow or cure this process. We hypothesize that chronic neuroinflammation drives the development of CTE. In this proposal, we plan to use an animal model of CTE to test a new drug that downregulates neuroinflammation to determine whether it can block the development of CTE. If successful this will be the only treatment available for patients with this disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Rehabilitation Research and Development SPiRE Program (RRDS)
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VA New Jersey Health Care System
East Orange
United States
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