The role of apolipoprotein E in recovery from traumatic brain injury and development of CHIMERA : a novel closed-head impact model of engineered rotational acceleration

Traumatic brain injury (TBI) is a “silent epidemic” that currently lacks any effective treatment. While a major health care problem in itself, TBI also increases Alzheimer’s disease (AD) risk and leads to the deposition of neurofibrillary tangles and amyloid deposits similar to those found in AD. Agonists of Liver X receptors (LXRs), which regulate the expression of many genes involved in lipid homeostasis and inflammation, improve cognition and reduce neuropathology in AD mice. One pathway by which LXR agonists exert their beneficial effects is through ATP-binding cassette transporter A1-mediated lipid transport onto apolipoprotein E (apoE). In the first part of this thesis, I show that a short-term treatment with synthetic LXR agonist GW3965 improves post-injury outcomes in mice subjected to closed-head, mild, repetitive weight drop TBI (mrTBI). My results suggest that both apoE-dependent and apoE-independent pathways contribute to the ability of GW3965 to promote recovery from mrTBI. While many drugs have shown promising outcomes in preclinical TBI models, clinical drug trials for TBI so far have failed, suggesting that the translational potential of TBI models may require further improvement. As most human TBIs result from impact to an intact skull, closed head injury (CHI) rodent models are highly relevant. Traditional CHI models like weight drop however suffer from large experimental variability that may be due to poor control over biomechanical inputs. To address this caveat we developed a novel CHI model called CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration) that fully integrates biomechanical, behavioral, and neuropathological analyses. CHIMERA is distinct from existing neurotrauma model systems in that it uses a completely non-surgical procedure to precisely deliver impacts of prescribed dynamic characteristics to a closed skull while enabling kinematic analysis of unconstrained head movement. Here I show that repeated TBI in mice using CHIMERA mimics many features of the human TBI including neurological, motor, and cognitive deficits along with persistent neuroinflammation and diffuse axonal injury, and increased endogenous tau phosphorylation up to 14 days with a reliable biomechanical response of the head. This makes CHIMERA well suited to investigate the pathophysiology of TBI and for drug development programs.Medicine, Faculty ofGraduat