One of the prominent pathological features of traumatic brain injury (TBI) is the accumulation of hyperphosphorylated and aggregated tau species in the brain. Tau is a cytoplasmic protein which is believed to be restricted to the intracellular compartment of neurons. However, several recent studies have investigated the existence and role for tau in the extracellular compartments of the brain, and have indicated that increased levels of monomeric tau in the extracellular environment play a major role in the pathogenesis of neurodegenerative tauopathies. In fact, it has been reported that extracellular tau levels in the brain correlate with clinical outcome in TBI. Despite the prevalence and potential importance of extracellular tau in neurodegenerative disease, there is little understanding of how extracellular tau is processed and eliminated from the brain. Our studies demonstrate that brain vascular mural cells (pericytes and smooth muscle cells) are involved in the processing and elimination of extracellular tau. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell expression following repetitive mild TBI (r-mTBI) in mice. Moreover, isolated brain vessels from r-mTBI animals were less able to internalize and process tau than non-injured animals. To our knowledge, these are the first studies to observe perturbations in mural cell expression and tau processing in the context of brain trauma. Importantly, alongside the mural cell disruptions in our mouse r-mTBI model, we observed an accumulation of total tau, phosphorylated tau, and oligomeric tau species in the brain. Additionally, we showed that tau elimination from the brain is reduced in transgenic mural-cell depleted animals compared to wild-type mice. We propose that brain vascular mural cells serve as a pathway for processing and eliminating tau from extracellular brain fluids and that disruption of these cells in TBI leads to tau pathology and neurodegeneration. The objective of this project is to determine the contribution of brain vascular mural cells to the tau pathology observed in TBI.
The specific aims of this proposal are, 1) examine mural cell status and tau pathology in mural-cell depleted animals and human TBI brains, 2) evaluate the role of mural cells in tau degradation and elimination and the impact of r-mTBI on these processes, and 3) determine the role of mural cells in paravascular (glymphatic) tau clearance and perivascular tau drainage from the brain following r-mTBI. To determine mural cell status following TBI, tau uptake and various mural cell markers will be examined in isolated cerebrovasculature from mural-cell depleted animals and human TBI brain specimens. To understand the influence of mural cells on tau disposition, tau degradation will be evaluated in isolated brain vasculature from r-mTBI animals and tau elimination from the brain will be examined in mural-cell depleted animals and r-mTBI mice. Lastly, to understand the impact of mural cells on extracellular tau movement in brain fluids following r-TBI, we will examine both paravascular (glymphatic) tau clearance and perivascular tau drainage from the brain in mural-cell depleted animals and r- mTBI mice. The proposed studies will advance our understanding of tau processing and elimination from extracellular brain fluids and determine the contribution of brain vascular mural cells to tau pathology and the neurodegenerative phenotype following TBI.
Traumatic brain injury (TBI) is a serious public health problem with over 2.5 million injuries occurring in 2010 alone. TBI is a regarded as a signature wound for many Veterans, with the rate of TBI among troops reported to be as high as 33%. Furthermore, the propensity for head injuries sustained in combat has placed our Veterans at even greater risk for developing neurodegenerative disorders such as Alzheimer?s disease (AD), highlighting the urgency to understand the causal factors that can be targeted to prevent or treat affected Veterans. At the moment, there are no effective disease-modifying therapies available for TBI or AD, and there is a clear, unmet need for novel strategies to treat these disorders. The current proposal will investigate a critical biological mechanism that contributes to disease progression following TBI, with the purpose of identifying new treatment strategies for this disorder, which will improve the welfare of our Veteran population.
