Effect of pericyte stimulation on traumatic brain injury pathophysiology

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Brain vascular pericytes are an essential component of the neurovascular unit and perform a number of diverse functions in regulating brain homeostasis. A common feature of many neurodegenerative disorders is a progressive disruption of vascular pericytes in the brain. The current studies observed pericyte degeneration in the brain at several time points following repetitive mild traumatic brain injury (r-mTBI) in mice. The influence of head trauma on the pericyte population may be the result of disruptions in the PDGF (platelet- derived growth factor) pathway. The interaction between the PDGF-BB ligand and the PDGFR-beta receptor is tightly regulated and required for pericyte function and survival. The current studies also found PDGF-BB levels in the brain were significantly diminished in r-mTBI mice and human TBI specimens. Thus, as pericyte health is highly dependent on stimulation of the PDGF pathway, the diminished availability of PDGF-BB in the brain following TBI may be driving pericyte degeneration post-injury. Moreover, given the role of pericytes in white matter homeostasis, extracellular tau disposition, and neuroinflammation, the deterioration of the pericyte population following head trauma could be a major driver of TBI pathophysiology. The hypothesis of this proposal is that stimulation of the PDGF pathway will improve pericyte function and mitigate the TBI phenotype. The objective of the proposed studies is to comprehensively evaluate the effect of PDGF-BB stimulation on TBI pathophysiology and cognitive dysfunction, as outlined in the following Aims, 1) investigate the effect of PDGF-BB on oligodendrocyte precursor cell (OPC) differentiation and remyelination following r- mTBI, 2) evaluate tau degradation and elimination in the r-mTBI brain upon PDGF-BB stimulation, 3) examine pericyte-mediated neuroinflammation in r-mTBI following PDGF-BB stimulation, and 4) determine the influence of chronic PDGF-BB stimulation on r-mTBI pathophysiology and cognitive behavior. To evaluate the effect of PDGF-BB stimulation in each of these Aims, the proposed studies will examine OPC differentiation in conditioned media from r-mTBI microvessels and assess remyelination in r-mTBI brains. For tau elimination, the tau degradation profile in isolated r-mTBI microvessels will be examined in addition to tau residence time in the brain of r-mTBI mice. For neuroinflammation, the proposed studies will identify the immunomodulatory factors secreted by r-mTBI pericytes, and the response of brain pericytes to TBI-relevant inflammatory stimuli. Lastly, the effect of a chronic PDGF-BB treatment paradigm on TBI pathophysiology and neurobehavior will be evaluated in r-mTBI animals. Collectively, this project will determine the contribution of brain pericyte degeneration to white matter deficits, tau accumulation, and neuroinflammation following head trauma. Moreover, the effect of PDGF-BB stimulation in mitigating these pathological features and cognitive dysfunction will be assessed following r-mTBI, which may provide a novel strategy for the treatment of brain injuries and potentially other neurodegenerative disorders.