TBI-Induced Disruption of Brain Drainage as a Mechanistic Driver of AD Pathogenesis
Abstract
One of the greatest environmental risk factors for developing Alzheimer’s disease (AD) later in life is traumatic brain injury (TBI). TBI not only significantly increases one’s risk of developing AD, but has also been linked to earlier onset and more aggressive disease progression. Despite being a major risk factor for AD, how brain injury mechanistically contributes to neurodegenerative disease development later in life has not been formally established. Proper removal of cellular debris and protein aggregates from tissue via the lymphatic drainage system has been shown to be required to maintain healthy organ function. Until 2015, it was thought that the brain lacked such a lymphatic drainage system and thus the processes by which the brain cleanses itself of neurotoxic agents were poorly understood. However, a major breakthrough was made with the recent discovery of central nervous system (CNS) lymphatics that drain macromolecules and cellular debris from the brain. Interestingly, emerging evidence suggests that defects in this brain drainage system can result in impaired clearance of neurotoxic agents widely believed to be major drivers of AD and other forms of dementia. For instance, over the last few years, it has been reported that breakdown in this brain lymphatic drainage system can cause impaired clearance of amyloid beta aggregates and extracellular tau from the brain. Despite these exciting recent findings linking brain lymphatic dysfunction to the neuropathology underlying AD, it remains to be formally established whether TBI-driven lymphatic demise mechanistically contributes to the heightened risk of developing AD following head trauma, TBI being a significant risk factor for developing AD later in life, and the heightened risk of developing AD associated with brain trauma. Therefore, in this project, we will interrogate a novel role for TBI-induced lymphatic dysfunction in driving AD pathogenesis. In our recent studies, we have found that even mild forms of brain trauma can cause severe and long-lasting impairments in brain lymphatic drainage. Our work also provides evidence that pre-existing lymphatic dysfunction, as may occur with repetitive head injury and aging, predisposes the brain to more severe TBI-induced neuroinflammation and cognitive decline. Moreover, we find that rejuvenation of brain lymphatic drainage function is effective in limiting TBI-driven neuroinflammation. Given these collective findings, we hypothesize that TBI-induced impairments in brain lymphatic function lead to impaired clearance of neurotoxic agents from the brain and that this can subsequently instigate more aggressive AD pathogenesis. To test our working hypothesis, we will determine how pre-existing brain lymphatic dysfunction as well as the rescue of defective lymphatic function impacts the ability of TBI to influence both Abeta-mediated neurological disease and tauopathy in experimental models of AD. Findings from this work will provide conceptual advancement in our mechanistic understanding of how TBI can lead to increased risk of developing AD later in life. Moreover, findings generated from the proposed studies are of significant translational value to the military and Veteran communities, as they will test the efficacy of targeting the brain drainage system to limit the ability of TBI to promote AD-associated neuropathology and cognitive dysfunction. The lack of defined guidelines for when individuals can safely return to high-risk activities following head trauma is also a significant problem for TBI caregivers. Our preliminary findings indicate that TBI can have especially deleterious consequences if this brain drainage system has not fully recovered prior to secondary brain trauma. Importantly, these findings suggest that evaluating brain lymphatic drainage recovery post-injury may provide a potential diagnostic strategy to inform military personnel of when it is safe to return to high-risk activities following
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110788
Entities
People
- John Lukens
Organizations
- United States Army
- University of Virginia