Alpha Omega Alpha Honor Medical Society

2015 Research Abstract

Assessing the Therapeutic Potential of Epothilone D and an Apolipoprotein E mimetic peptide in a Murine Model of Chronic Traumatic Encephalopathy

Investigator: Alexandra Rosenberg, Duke University School of Medicine

Mentor(s): Daniel Laskowitz, MD; Hana Dawson, PhD

Background: Repetitive mild traumatic brain injuries (TBIs) may increase the risk of developing chronic traumatic encephalopathy (CTE), a progressive neurodegenerative process that is clinically associated with memory disturbance, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. While the pathophysiology of CTE is not fully established, deposition of phosphorylated tau and chronic neuroinflammation are believed to play contributing roles. This experiment sought to find a potential therapeutic for CTE. Endogenous apolipoprotein E, which is synthesized in the brain and upregulated after injury, helps suppress neuroinflammatory responses. This was the rationale for creating a small apoE mimetic peptide that retained the immunosuppressive effects of the intact apoE protein, but was optimized for CNS penetration. Preclinical studies conducted by this lab demonstrated that this novel ApoE-mimetic peptide has lasting neuroprotective effect when administered after severe TBI and other acute neurological injuries, and thus might be similarly effective in limiting the chronic neuroinflammation believed to contribute to CTE. A second therapeutic, Epothilone D (EpoD), was also tested. EpoD is a microtubule stabilizing compound that has shown promise in treating tauopathies such as Alzheimer’s disease, and thus we hypothesized it might offset the development of the toxic CNS tau aggregates believed to contribute to the development of CTE.

Methods: This experiment sought to assess whether treatment of a repetitive TBI mouse model of CTE with novel therapeutics EpoD or an ApoE mimetic peptide would improve longterm cognitive and motor function. Our lab has developed a reproducible murine model of CTE that captures the chronic and delayed progressive neuropathology of that condition. We administered a mild repetitive TBI at weekly intervals for 4 weeks. Treatment groups received either ApoE peptide at 0.5 mg/kg or EpoD at 1.0mg/kg (both intraperitoneally) at 30 minutes and 72 hours after each weekly. Vestibulomotor function was tested via Rotarod latency at intervals up to 3 months post-injury; cognitive function was tested with the Morris Water Maze.

Results: A generalized linear model comparing the placebo and treatment groups over time demonstrated that the ApoE-group’s motor performance was significantly different over time (p=0.015). ApoE-treated mice also showed significantly less hippocampal microgliosis. In contrast, EpoD-treated mice did not have histologic or motor results significantly different from placebo. Cognitive function as assessed by the Morris water maze did not show significant difference between either treatment group from placebo mice.

Conclusion: Our results suggest that an ApoE-mimetic peptide is a promising therapeutic to treat the chronic motor deficits caused by repetitive TBIs.

Last modified: 9/11/2015

Updated on September 11, 2015.

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