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Traumatic brain injury (TBI) is recognized as the strongest environmental risk factor for neurodegenerative disease, including dementia of Alzheimer's disease (AD)-type. Correspondingly, the neuropathology of survival from TBI comprises a complex array of pathologies, including production and deposition of amyloid-beta (A?) often in association with axonal degeneration. Of particular note, pathologies in A? are recognized across all survival intervals, being present in patients dying in the acute phase post injury, in a proportion of longer term survivors of moderate to severe TBI and in a majority of patients with later stage, clinically significant CTE. Derived from amyloid precursor protein (APP), soluble A? is widely recognized as neurotoxic. As such, A? clearance is closely regulated via enzymatic degradation, direct absorption into blood and perivascular drainage. As a consequence, TBI-associated pathologies in A? may arise through either excess production, inefficient clearance or a combination of both. A feature common to all severities of TBI is diffuse axonal injury (DAI). As a consequence, there is interruption of axonal transport in damaged axons, which we have demonstrated is associated with rapid accumulation of APP and the secretases responsible for its processing to A?. Thus, within hours of TBI, there is the potential for release of large pools of neurotoxic A? as a consequence of DAI. Of note, among our most recent observations, we have demonstrated that axonal transport interruption is not restricted to the acute phase after injury, with evidence of continued axonal degeneration and associated APP transport interruption in material from survivors a year or more from TBI. As such, through axonal injury there is potential for TBI to initiate immediate and sustained A? production. However, though DAI is ubiquitous and may persist years after injury, only around 30% of patents develop A? plaque in the acute phase after TBI; these acute plaques appearing to diminish in the months following injury. In brain parenchyma, the principal enzyme responsible for A? degradation is neprilysin. Intriguingly, through our unique studies in human TBI, we have shown polymorphism in the neprilysin gene is associated with risk of amyloid plaque deposition in the acute phase post TBI. However, its relationship to late post-TBI pathologies is unknown and will be addressed in this proposal. In addition to enzymatic catabolism, clearance of soluble A? proceeds via exchange across the blood brain barrier (BBB) and through interstitial fluid drainage along perivascular pathways. In this regard, our preliminary studies in both human tissue and animal models suggest TBI is associated with significant and persisting BBB disruption in a high proportion of patients. As such, disturbance in the vasculature following TBI, might serve to alter A? transport across the BBB following injury. Our proposal extends our longstanding and successful collaboration between investigators at the University of Pennsylvania and University of Glasgow, UK. We propose to utilize the unique and comprehensive tissue resources of the Glasgow TBI Archive, which we will interrogate in studies directed to understanding processes contributing to A? genesis and clearance after injury across a spectrum of survivals. In parallel, through our well- characterized large animal model of TBI, we will pursue studies to determine the cellular and molecular mechanisms contributing to disturbance in A? processing and vascular injury after TBI. As TBI associated neurodegenerative disease is increasingly recognized as a major health concern, there is a clear and pressing need to better understand the persistent and evolving pathologies arising from injury to direct targeted strategies for diagnosis and intervention, which this series of integrated, bidirectional, translational studies directed towards characterizing A? processing following TBI seeks to address.
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