VEGF-C treatment enhances meningeal lymphatic drainage after mild traumatic brain injury and protects against tau pathology, microgliosis and neurodegeneration in a mouse model of tau pathology.

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 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 hours 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. Overall design: PS19 mice were subjected to (1) Sham vs. controlled cortical impact (mild TBI, right hemisphere), and were treated with (2) AAV-GFP control vs. AAV-VEGFC. Hippocampi were microdissected from brains, flash-frozen, and nuclear RNA was analyzed via scRNA-sequencing.