Influence of APOE Genotype on the neurodegenerative sequelae of repetitive mild TBI in an hTau mouse model. - 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.
