The Effects of Genetic Polymorphisms on Recovery After Repeated Mild Traumatic Brain Injury in a Mouse Model and Personalized Treatment Approaches

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Abstract

Traumatic Brain Injury (TBI) is a serious and potentially life-threatening clinical problem. In 2013, there were 2.5 million TBIs in the United States, 50,000 of which led to death and 70,000 of which led to permanent neurological damage. Clinicians have long noticed that certain patients have worse recovery than others after TBI and identifying what makes some patients more susceptible is a vital step in understanding the underlying mechanisms through which TBI causes its deleterious effects. In this study, we sought to determine the effect of specific single nucleotide polymorphisms (SNPs) on recovery after TBI, and to investigate the underlying mechanisms that may be a factor. This knowledge can be used to explore personalized approaches to treatment of TBI. We have investigated cellular and behavioral outcomes in genetically engineered mice with either the Brain-derived neurotrophic factor (BDNF) Val66Met or ApoE4 polymorphism following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. We have found that relative to injured Val66Val and ApoE3 carriers, injured Val66Met and ApoE4 carriers have a larger injury volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post injury (DPI) as well as altered levels of BDNF. As a result, we have concluded that the ApoE4 and the Val66Met genetic polymorphisms are a risk factor for poor outcomes after rmTBI. Using this information, we developed a personalized approach to treating genetically susceptible individuals by targeting the pathway altered in those genotypes. In the Val66Met mice, we used an AAV-BDNF virus to overexpress wildtype BDNF in the cortex and hippocampus and investigated outcomes at the 21 DPI timepoint. In the ApoE mice, we used Bryostatin-1, a PKCε activator that has been shown to rapidly increase BDNF levels, and investigated outcomes at the 1 DPI timepoint. We have shown that these interventions are able to improve cellular as well as motor and cognitive behavior outcomes at these timepoints. This study lays the groundwork for further investigation into the genetics that play a role in recovery after rmTBI and highlights the role that personalized therapeutics may be able to play in recovery for susceptible individuals.

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