Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis.

Traumatic brain injury (TBI) increases one's risk of developing Alzheimer's disease and tauopathy. Yet, the mechanisms linking TBI to neurodegenerative disease remain poorly defined. Mounting recent evidence indicates that defects in brain lymphatic drainage contribute to multiple neurodegenerative diseases. Here, we investigated whether promoting brain lymphatic drainage recuperation following TBI via treatment with the lymphangiogenic factor vessel endothelial growth factor C (VEGFC) mitigates the ability of TBI to exacerbate tauopathy. In this study, we show that a single mild TBI leads to worsened neuropathology, brain macrophage activation, and neurodegeneration in the PS19 mouse model of tauopathy. Moreover, we find that viral-vector-based delivery of VEGFC into the meningeal compartment 24 h post-TBI ameliorates tau-mediated neurodegenerative disease pathogenesis. Findings from these studies offer new insights into how TBI leads to the development of tauopathy later in life and suggest that VEGFC-based treatments might offer a therapeutic strategy to limit tauopathy after sustaining a head injury.