Glial Cell Dysfunction in Neurodegenerative Sequelae of Repetitive Mild Traumatic Brain Injury
Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity among both military personnel and the civilian population and is the leading cause of death and disability in the under-45 age group in industrialized countries. Among the soldiers who survive conflicts in Iraq and Afghanistan, TBI accounts for a larger proportion of their casualties than in any other war in recent US history. Furthermore, among patients evaluated at the Walter Reed Hospital, closed head injuries significantly outnumber other penetrating injuries, and 84% of TBIs occur in a non-deployed setting involving vehicle crashes, falls, sports, and military training activities (Defense and Veterans Brain Injury Center statistics). It is estimated that over five million Americans are living with disabilities resulting from TBI. TBI has long been recognized as a risk factor for later life Alzheimer s disease and neurodegeneration, but mild TBI (the most common TBI) is now recognized to be a major health concern for both civilian and military populations. Repetitive injuries are of particular concern, with apparent cumulative effects on outcomes, and in recent years the debilitating neurodegenerative condition known as chronic traumatic encephalopathy (CTE) has been particularly associated with a history of repetitive mild TBI. For many years TBI has been known to be a risk factor for later life neurodegenerative diseases, such as Alzheimer s disease or related disorders, but the precise nature of how TBI leads to or precipitates these conditions is not understood. Why do some individuals develop features of Alzheimer s disease while others develop pathology consistent with CTE? Is there, in fact, a TBI neurodegenerative disease in and of itself, distinct from existing diagnoses (which would be consistent with clinical observations)? What influences act on TBI neurodegeneration to allow emergence of features reminiscent of Alzheimer s disease, fronto-temporal dementia, CTE or related conditions? Clinical studies in human TBI patients are insufficient at this time to answer these questions and are hampered by the variation inherent in any human population studies (age, gender, ethnicity, medical history), as well as the diversity of ways in which a TBI, or TBIs, can be sustained. They are mostly inadequate, however, because of our inability to examine molecular level TBI consequences in the brain during life, restricted as we are to a single timepoint of investigation at autopsy. Thus, we must turn to animal models in which we can profile the brain s response to injury over time. We have spent years developing and characterizing mouse models of repetitive mild TBI that demonstrate lifelong behavioral and neuropathological features of human TBI and are thus relevant models in which to generate data that will translate to human patients. Our data show the critical importance of neuroinflammation following TBI, which represents a key therapeutic target as, despite the previously mentioned variables in TBI patient populations and indeed, across laboratory models of TBI, neuroinflammation is a common denominator across all patients and models. Specifically, we observe dramatic increases in the inflammatory cells known as microglia, and these increases last for life, although they can be temporarily suppressed in response to anti-inflammatory treatments. Thus, we consider a deeper investigation of microglial responses to injury over time to an important area for understanding TBI pathogenesis. Given the seminal role of microglia in neuroinflammation, we hypothesize that TBI induces an altered homeostasis in microglia, which persists long after the original insult and influences many other brain molecular mechanisms forthwith. These changes drive neurodegenerative processes, increase the brain s vulnerability to subsequent insult, and contribute to precipitation of known neurodegenerative diseases. Significantly, we have also demonstrated tau protein path
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810811
Entities
People
- Fiona Crawford
Organizations
- Roskamp Institute
- United States Army