title: Therapeutic Target Identification Through Analysis of Microglial Driven Traumatic Brain Injury Pathogenic Mechanisms
Creators: name: Pearson, Andrew
Publisher: name: The Open University
Year: 2022

description: Exposure to repetitive mild traumatic brain Injury (r-mTBI) is a substantial risk factor for the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). Neuroinflammation is a central component in the secondary injurious response to r-mTBI and has been shown to strongly influence long-term cognitive and functional outcomes following brain injury. As the resident innate immune cells of the CNS, microglia are intricately involved in the neuroinflammatory response that follows TBI. While neuroinflammation has several beneficial functions and is crucial in initiating repair pathways, chronic dysregulated microglial activation and neuroinflammation can propagate further neuronal damage, ultimately leading to neuronal death. Unfortunately, despite mounting evidence linking r-mTBI with progressive neurodegenerative pathologies, there are currently no disease-modifying treatments available to mitigate the consequences of r-mTBI. The persistent nature of microglial activation and neuroinflammation following r-mTBI represents a valuable opportunity to interrogate the mechanisms driving microglial dysfunction. Therefore, in this thesis, I sought to identify microglial-specific therapeutic targets and evaluate their potential to ameliorate the chronic neurodegenerative sequelae of r-mTBI. To achieve this aim, I established and characterized a pre-clinical model of r-mTBI that recapitulates the cognitive deficits, and chronic neuroinflammation observed clinically. Furthermore, I demonstrate that microglia are critical drivers of the neuroinflammatory response to r-mTBI, and through a comprehensive analysis of the microglial transcriptome at sub-chronic and chronic time points I identified dysregulated PPARy signaling as a critical regulator of microglial dysfunction following chronic exposure to r-mTBI. PPARγ is a nuclear transcription factor that is well expressed in immune cells such as microglia. However, there is limited understanding of how PPARy signaling influences microglial pathobiology in the chronic aftermath of repetitive head trauma. To address this, I first investigated how PPARy agonism can influence microglia-mediated inflammation using an in vitro microglial cell model where I found that the PPARy agonist, Pioglitazone, demonstrated beneficial effects on markers of inflammation and microglial metabolism. Furthermore, I assessed the therapeutic potential of a delayed treatment paradigm using Pioglitazone, wherein I observed that treatment reduced microglial-mediated neuroinflammation and ameliorated the cognitive and pathological consequences of r-mTBI. Future studies stemming from this thesis will focus on using cell-specific transgenic models to further investigate the contributions of PPARy signaling to microglial pathobiology following chronic exposure to r-mTBI. Together this collective work has revealed the potential of PPARy as a tractable and viable novel target for neurodegenerative diseases whereby inflammation is a common denominator.