Role of Nonneuronal Cells in Tauopathies After Brain Injury
Abstract
Prior head trauma (traumatic brain injury or TBI), even when mild in severity, appears to increase risk for Alzheimer s disease (AD) and chronic traumatic encephalopathy (CTE), neurodegenerative diseases that may emerge many years after patients appear to have recovered from their initial injury. However, it remains unclear why there is such a long delay between the inciting TBI(s) and the onset of the cognitive and behavioral symptoms that characterize AD and CTE. One potentially important clue to this puzzle is that TBI, CTE, and AD are each associated, through various and overlapping mechanisms, with abnormal brain inflammation, which activates two kinds of glial cells (astrocytes and microglia). Inflammation appears to be closely related to AD, as people with a history of long-term use of nonsteroidal anti-inflammatory drugs are less likely to develop AD, while people with genetic mutations that lead to abnormal function of inflammatory cells like microglia are more likely to develop AD. Another common feature of both AD and CTE is the accumulation of aggregates of the tau protein, which is normally important for maintaining the structure of nerve cells. Tau protein is the major component of the abnormal neurofibrillary tangle and glial tangle lesions seen in the brains of AD and CTE patients. Despite compelling evidence that repeated mild brain injury could cause persistent brain inflammation, tau aggregation, and subsequent major cognitive, behavioral, and/or motor problems, we still do not understand the connections between these events. One major obstacle is the lack of appropriate mouse models for brain inflammation in these situations. First, brains from AD and TBI patients demonstrate high levels of inflammatory molecules that are virtually absent in the analogous mouse and rat models. Perhaps unsurprisingly, their deficits are typically much less severe than those seen in human patients. Second, abnormal production of tau protein is likely to be critically related to chronic brain changes after TBI in humans. However, mouse tau does not appear to form tangles like those seen with human tau, and even when mice are genetically modified to make human tau, its production would need to respond to injuries in the same fashion as normal mouse tau would. Third, experimental TBI needs to be consistent across animals in order to accurately compare the short-term and long-term effects of these injuries in under different conditions. This proposal attempts to overcome each of these issues and increase our understanding of brain inflammation in these interrelated diseases. The main difference in brain inflammation between humans and mice is that only humans fully activate a toxic cascade of interacting proteins called complement factors. The first protein in the cascade, complement C1q, binds tau aggregates in AD patients and activates the rest of the system to generate toxic molecules and form a membrane attack complex (MAC) that damages brain cells. Mouse C1q does not fully activate this system, and in particular, does not increase C5a (which amplifies inflammation) and C5b (part of the MAC). This may explain why mice making both normal human tau and tau aggregates have much lower rates of brain cell loss than human AD patients. Therefore, this proposal investigates the relationships between TBI, brain inflammation and tau pathology in mice that make human tau along with either human C5a (Aim 1) or human C1q (Aim 2). This proposal addresses multiple gaps in our knowledge about AD and TBI: (1) We test the hypothesis that factors involved in normal brain function (C1q or astrocytes) may regulate abnormal tau accumulation; (2) we investigate the poorly understood role of complement factor associated inflammation in tau-related brain disease; and (3) we identify the different roles of microglia and astrocytes in tau-related brain disease. All of our studies will use genetically modified mice that ma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510422
Entities
People
- Sally A Frautschy
Organizations
- United States Army
- University of California, Los Angeles