Traumatic brain injury (TBI), often referred to as the ?silent epidemic,? is widely discussed in the news today. The military loses thousands of man-years in experience due to the effects of TBI in soldiers, including those prematurely returned to active duty, as well as soldiers who cannot return to service. In the civilian population, closed head or concussive injury is also one of the leading causes of death and disability. Many young adults never regain premorbid skills or responsibilities after TBI despite intensive and comprehensive rehabilitation efforts on their behalf. The sequelae of TBI are a mixture of cognitive psychomotor and emotional (psychiatric) signs and symptoms, and the emotional and psychological burden on patients and caregivers can be enormous. Mild TBI (mTBI) accounts for the majority of all TBI cases and the devastating neurodegenerative outcomes of repetitive mild TBI (r-mTBI) have emerged over the last few years. The negative sequelae of r-mTBI pathogenesis will often already be well underway by the time interventions are sought, and there are currently no effective treatments. There is a clear need for improved and increased modeling of mTBI in the laboratory, to enable the dissection and evaluation of r-mTBI-dependent molecular responses and identification of better approaches to mitigate the negative outcomes. We have developed several different mouse models of repetitive mild TBI, with different neurobehavioral, neuropathological and biochemical outcomes. They recapitulate features of human TBI and are thus of relevance to a translational platform. We now propose to increase the translational relevance of our model by working with mice expressing both human Tau and apoE proteins (hTau/APOE mice), both of which have been demonstrated to significantly influence TBI pathogenesis. APOE genotype, a known risk factor for Alzheimer's Disease, has long been discussed as a risk factor for poor outcome after TBI. In addition to characterizing the new model we propose hypothesis-driven investigations of three mechanisms which our preliminary data, and published research, suggest as the means (individually or interactively) through which APOE genotype contributes to TBI outcome ? specifically neuroinflammation, lipid dysregulation and clearance of tau from the brain. This work will reveal particular molecular pathways as therapeutic targets for r-mTBI drug discovery, and owing to the discoveries being made in the hTau/APOE model. we expect these results to be of more translational relevance and value to the TBI patient population.
Repetitive mild TBI (r-mTBI) is one of the strongest risk factors for the development of neurodegenerative diseases, and this can be further compounded by APOE genotype, with worse outcome reported amongst E4 allele carriers. In this study we will utilize humanized tau and APOE mouse models of chronic r-mTBI to investigate the influence of APOE genotype on the neurodegenerative sequelae of r-mTBI. Based on our preliminary findings we will specifically explore three main pathobiological areas, namely the influence of APOE on neuroinflammation, lipid profiling and tau clearance mechanisms following chronic r-mTBI; from these studies we aim to provide a very comprehensive evaluation of mTBI pathogenesis unique to APOE genotype that may lead to novel, tractable targets for future studies of novel therapeutic approaches.
