Cerebrovascular Degeneration Following Repetitive Mild Traumatic Brain Injury Contributes to Tau Deposition in the Brain
Abstract
The current submission meets the intent of the FY21 TBIPHRP Investigator-Initiated Research Award (IIRA) mechanism, as the proposed studies will address the Treatment Focus Area by investigating a potential treatment paradigm that promotes recovery and improves the long-term outcomes following traumatic brain injury (TBI). Specifically, the current proposal will address several FY21 TBIPHRP IIRA sub-areas by evaluating the impact of a novel therapeutic approach on TBI pathology and the long-term outcomes following TBI, such as neurodegeneration and dementia. It is anticipated these findings will not only foster new approaches to treat individuals afflicted with these disorders, but also advance our understanding of the influence of TBI on psychological health. While many of the features resulting from head trauma can 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 psychological disorders and dementia, such as 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 TBI and other neurodegenerative disorders such as 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, such as disease 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 and psychological decline. A common feature of many neurodegenerative disorders, including AD, is a loss of cells within the cerebrovasculature, particularly brain pericytes. Our prior reporting demonstrated that brain pericytes have a role in the processing and elimination of extracellular tau in the brain, and like other neurodegenerative disorders, we found that the pericytes in the brain progressively degenerate following head trauma. Our 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. Investigation of these phenomena could improve our understanding of the interrelationship between TBI and the development of psychological disorders and dementia, such as 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 after 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 th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210802
Entities
People
- Corbin Bachmeier
Organizations
- Roskamp Institute
- United States Army