Microglial NOX2/NLRP3 Inflammasome Activation Drives Tau Pathology and Cognitive Impairments in Chronic Traumatic Brain Injury
Abstract
This proposal involves a highly synergistic collaboration between Dr. Joseph Ojo (Roskamp Institute, Florida) and Dr. David Loane (Trinity College Dublin, Ireland). We will conduct impactful preclinical research to directly addresses the Fiscal Year 2022 Peer Reviewed Alzheimer’s Research Program Investigator-Initiated Research Award focus on Foundational Research understanding of the mechanisms for Alzheimer’s disease (AD) and AD-related dementias (ADRD) after traumatic brain injury (TBI). Specifically, we will interrogate pathogenic mechanisms of chronic neuroinflammation following exposure to single severe TBI (ssTBI) or repetitive mild TBI (r-mTBI), how they can contribute to the development of tau seeding and chronic neurodegenerative diseases, and whether selectively targeting these mechanisms can improve long-term recovery. TBI is the leading cause of death and morbidity in the under-45 age group in industrialized countries. In the U.S., over five million Americans are estimated to be living with disabilities resulting from TBI. Among the Soldiers who survived Iraq/Afghanistan conflicts, TBI accounts for a larger proportion of their casualties than in any other war in recent U.S. history. TBI can be classified as severe, moderate, or mild. Severe TBI is the least frequently occurring type of TBI but represents the patient population with the highest rate of mortality and morbidity. Patients who suffer from a severe TBI (e.g., penetrating injury, cerebral lacerations, or contusions) display macroscopic changes to the brain typified by bleeding, bruising, or swelling. These patients also exhibit a prolonged length of altered consciousness and memory loss, and those who survive show a plethora of neurological and psychological symptoms akin to neurodegenerative disease that can last for a lifetime. Many young adults never regain premorbid skills or responsibilities despite intensive and comprehensive rehabilitation efforts on their behalf. There is also a significantly increased risk of suicide (by 2.45-fold) compared to those with no TBI diagnosis. Mild TBI (mTBI) or closed head injuries significantly outnumber severe TBI and other penetrating injuries. Eight-four percent of TBIs among patients evaluated at the Department of Veterans Affairs (VA) occurs in a non-deployed setting involving vehicle crashes, falls, sports, and military training activities (Defense and Veterans Brain Injury Center statistics). In particular, the deleterious effects of repetitive mTBI (r-mTBI) in the last decade has received more attention because of the link between exposures to repeated concussions in contact sports and the development of chronic traumatic encephalopathy. r-mTBI is now recognized to be a major health concern for civilian and military populations, and mounting evidence suggests that r-mTBI may increase the risk for developing dementia-like symptoms where patients experience memory loss, executive dysfunction, and depression. To date, there are no disease modifying therapies for TBI of any severity. Current treatments for TBI focus on the primary consequences of the injury, such as brain swelling, because the chronic biological consequences of TBI are still mostly unknown. There are very few current clinical trials in the U.S. or worldwide which are specifically addressing mTBI, and typically the drugs under investigation were developed for other conditions and have shown very little success thus far, presumably due to the lack of knowledge of the molecular mechanisms that constitute the brain’s secondary response to TBI. These numerous and complex mechanisms may persist for months and even years after the event, and naturally are significant contributors to the patient’s overall outcome. To address this problem, we have developed and characterized mouse models of single severe TBI (ssTBI) and r-mTBI, which recapitulate many features of human TBI pathology and the heterogeneity of TBI in humans. In our models, w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310201
Entities
People
- Joseph Ojo
Organizations
- Roskamp Institute
- United States Army