Altered Brain Fluid Dynamics and Solute Elimination Following Repetitive Mild Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) is the result of a sudden trauma to the brain that significantly disrupts brain function. While many of the features resulting from the primary trauma tend to subside over time, more chronic events emerge in the aftermath of the initial trauma and evolve over several years or decades. One of the long-term consequences of repetitive head trauma is the development of dementia or Alzheimer’s disease (AD). While AD has always been a concern for our aging Veterans, the propensity for head injuries sustained in combat has placed our military personnel at even greater risk for developing AD than the general population. A prominent pathological feature of both TBI and AD is the accumulation of toxic tau protein aggregates in the brain. Recent studies have indicated these tau proteins can spread from cell to cell, and it is believed that increased levels of tau in the extracellular fluids of the brain play a major role in the progression of certain diseases. In fact, the concentration of tau in brain fluids can be used to predict adverse clinical outcomes following TBI. Likewise, extracellular tau levels in the brain have been shown to predict AD progression and cognitive decline. As such, understanding how tau is processed and eliminated from brain fluids may be important in determining the onset and development of neurodegenerative disease. A common feature of many neurodegenerative disorders, including AD, is a loss of cells within the cerebrovasculature, particularly brain pericytes. Our prior reporting demonstrated brain pericytes have a role in the processing and elimination of extracellular tau in the brain, and like other neurodegenerative disorders, we found the pericytes in the brain progressively degenerate following head trauma. Our prior findings also showed that disruptions to the pericyte population following brain injury coincided with an accumulation of tau in the brain and the appearance of toxic tau species. As such, alterations within the pericyte population appear to contribute to tau pathology following head trauma and may be an important driver of neurodegeneration post-injury. Moreover, investigation of these phenomena could improve our understanding of the interrelationship between TBI and the development of AD. Despite the association between pericyte dysfunction and neurodegeneration, and the role of pericytes in extracellular tau elimination from the brain, there has been little investigation into the how brain pericytes process extracellular tau and whether these cells can be targeted to facilitate tau removal from the brain and improve TBI outcome. Through our preliminary studies, we identified specific pathways by which brain pericytes regulate the movement tau in extracellular brain fluids and contribute to tau elimination from the brain. We propose that stimulating brain pericytes following brain injury will improve pericyte function and promote the removal of extracellular tau from the brain. The objectives of the studies proposed in this application are to (1) examine the movement of tau in extracellular brain fluids post-injury following pericyte stimulation, (2) evaluate the influence of pericyte stimulation on cerebrovascular tau elimination from the brain following head trauma, and (3) determine the effect of pericyte stimulation on tau levels in the brain and the appearance of toxic tau species. At the moment, there are no effective disease-modifying therapies available for TBI and AD, and there is a clear, unmet need for novel strategies to treat these disorders. The current proposal will employ an innovative strategy by investigating the influence of pericyte dysfunction on TBI pathogenesis and evaluating a potential therapeutic approach to mitigate tau pathology following brain trauma. Completion of these studies will advance our understanding of the processes contributing to tau pathogenesis and neurodegeneration following head trauma and may identify new tr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210467
Entities
People
- Corbin Bachmeier
Organizations
- Roskamp Institute
- United States Army