Traumatic brain injury (TBI) is a risk factor for the development of Alzheimer?s disease (AD) and Alzheimer?s Disease Related Dementias (AD/ADRD). Although much work has been done in evaluating pathophysiological mechanisms of TBI and AD, the relationships between these two conditions is not completely understood. The role of inflammation in the pathophysiology of TBI and neurodegenerative diseases has been reported in the experimental and clinical literature. Accordingly, TBI and neurodegenerative diseases share many pathological and immunological hallmarks that indicate potential relationships that are critical as therapeutic strategies are developed. Recently, our laboratories, as well as others, have helped clarify the importance of abnormal inflammasome signaling in the pathogenesis of TBI and in the aging brain. These findings indicate that an innate inflammatory response plays a critical role in multiple pathophysiological events in neurodegenerative diseases such as AD. New evidence for the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)-specks from microglial cells has provided further evidence for inflammasome activation in AD. Importantly, ASC- specks with prion-like properties contribute to the deleterious effects of the innate immune response mediated by the inflammasome. The overall goal of the proposed studies is to determine mechanisms underlying TBI-induced inflammasome activation as a risk factor for AD and to evaluate targeted therapeutic approaches to improve outcomes in this patient population. Our central hypothesis is that inflammasome activation in AD augments TBI-induced inflammation by a mechanism, mediated in part by extracellular vesicle (EV) containing inflammasome proteins and ASC-speck accumulation, that contributes to worsened AD pathology and memory impairments. To test this hypothesis the following aims will be pursued: Aim 1) To determine the temporal profile and the mechanisms underlying the detrimental effects of TBI on inflammasome activation in AD mice; Aim 2) To investigate the role of abnormal inflammasome activation and ASC-specks in microglia as an underlying mechanism for the deleterious effects of TBI in AD mice and Aim 3) To determine the therapeutic effects of inflammasome inhibition and ASC-speck formation on histopathological and behavioral outcomes after TBI in WT and AD-transgenic mice. The proposed studies will provide new information on how specific genetic risk factors for AD may heighten TBI- induced neurodegenerative processes and lead to AD-related pathological and progressive cognitive decline. Moreover, these studies will advance current inflammasome research into the AD/ADRD field to elucidate novel mechanisms underlying how TBI contributes to the onset of neurodegenerative disorders, and provide a new direction for evaluating therapeutic interventions targeting abnormal inflammasome activation after TBI in AD-transgenic mice for potential translation to the clinic.
|Effective start/end date||9/20/21 → 8/31/23|
- National Institute of Neurological Disorders and Stroke: $1,126,479.00
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