Royo Marco, Ana, Microbiology - School of Medicine, University of Virginia0000-0002-2801-2746
Advisors
Lukens, John, MD-NESC Neuroscience, University of Virginia
Abstract
Traumatic brain injury is a significant global health burden and a leading environmental risk factor for the development of Alzheimer’s disease and related tauopathies, including chronic traumatic encephalopathy later in life. Despite extensive evidence linking head trauma to accelerated neurodegeneration, the mechanistic underpinnings relating TBI to progressive tau pathology remain poorly defined. Recent studies have highlighted the role of meningeal lymphatic vessels in mediating the drainage of cerebrospinal fluid and macromolecules from the brain. Dysfunction of this drainage network may contribute to the accumulation of neurotoxic proteins and chronic inflammatory mediators observed in neurodegenerative disease. This dissertation investigates how TBI-induced disruption of brain lymphatic function contributes to the progression of tauopathy and whether restoring this pathway can mitigate disease severity. Employing the PS19 transgenic mouse model of tauopathy, we demonstrate that even a single mild closed-skull TBI leads to impaired lymphatic drainage, elevated hyperphosphorylated tau, increased microglial/macrophage activation, and accelerated neurodegeneration accompanied by cognitive decline. Importantly, therapeutic boosting of meningeal lymphatic drainage via adeno-associated-virus-mediated delivery of vascular endothelial growth factor C (VEGFC) restored drainage function, reduced hyperphosphorylated tau, dampened neuroinflammatory responses, preserved neuronal and synaptic integrity, and improved cognitive outcomes. Single-nucleus RNA sequencing further revealed that VEGFC treatment promoted transcriptional programs associated with neuronal health and synaptic membrane integrity. Together, these findings link TBI, impaired meningeal lymphatic drainage function, and tauopathy progression. They further identify VEGFC-mediated lymphangiogenesis as a potential therapeutic strategy to prevent or attenuate the long-term neurodegenerative consequences of traumatic brain injury.
Royo Marco, Ana. Therapeutic VEGFC Treatment Provides Protection Against Traumatic Brain Injury-driven Tauopathy Pathogenesis. University of Virginia, Microbiology - School of Medicine, PHD (Doctor of Philosophy), 2025-12-05, https://doi.org/10.18130/zrmc-bs88.
