Tau Processing by Mural Cells in Traumatic Brain Injury and Alzheimer s Disease
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 a progressive neurodegenerative disorder termed chronic traumatic encephalopathy (CTE). A prominent feature of CTE is an abnormal accumulation of toxic tau protein aggregates. Recent work has revealed that tau is continually released from neurons into the fluids of the brain, under normal conditions, to extrude excess tau and avoid toxic levels from accumulating in the cell. However, when the brain is diseased or injured, the machinery that removes tau from the brain becomes dysfunctional and the toxic forms of tau begin to accumulate and damage the brain. One of the pathways responsible for the removal of solutes from the brain involves specialized cells associated with bloods vessels within the brain, called brain vascular mural cells. These cells capture solutes from fluids within the brain and degrade them into products that can be easily eliminated from the body. While these cells have an important role in the removal of a variety of molecules, the interaction between these cells and tau has not yet been investigated. Through our preliminary studies, we found that the mural cells associate with tau to a greater extent than other cells of the brain vasculature. To our knowledge, no other study has directly demonstrated an association between tau and brain vascular mural cells. The above studies indicate mural cells are involved in the brain disposition of tau and that depletion and/or dysfunction of these cells could potentiate tau pathology. Prior studies have demonstrated that mural cells are depleted in many brain disorders including Alzheimer s disease (AD). Due to the role of these cells in degrading and removing solutes from the brain, the loss of these cells in disease may explain the accumulation of toxic solutes that is observed in various brain disorders. Despite the significance of mural cells in the elimination of solutes from the brain and their diminished expression in brain disease, to our knowledge, no one has investigated the state of the mural cells in TBI. In our preliminary studies, we observed a progressive decline in brain mural cells after injury in our mouse model of TBI. Moreover, we found that isolated brain vasculature from these same TBI animals were less able to internalize and process tau than animals that did not receive a TBI. To our knowledge these are the first studies to observe changes in mural cell expression in TBI and alterations in the functional processing of tau following injury. It is also important to note that the findings in the TBI animals were consistent with our observations of mural cell depletion and dysfunctional tau processing in AD mice, which suggests this pathway represents a common link between TBI and AD, as it relates to tau pathology. The objectives of the studies proposed in this application are to (1) determine the role of the brain vascular mural cells in TBI and AD, (2) evaluate the interaction between brain vascular mural cells and tau, (3) identify the factors that cause mural cell disruption in TBI and AD, and (4) examine the association between brain trauma and the development of AD. In totality, our studies indicate mural cell disruption in TBI and AD may be an important factor in tau pathogenesis and neurodegeneration and could explain the association between head trauma and the development of AD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610724
Entities
People
- Corbin Bachmeier
Organizations
- Roskamp Institute
- United States Army