Glymphatic Dysfunction and Aquaporin-4 Dysregulation in Traumatic Brain Injury and Brain Tumors: A Review.

The glymphatic system is a cerebrospinal fluid-interstitial fluid exchange pathway that clears metabolic waste and maintains brain fluid homeostasis. Aquaporin-4 (AQP4), a water channel at astrocytic endfeet along the neurovascular interface, supports perivascular water transport and glymphatic flow. Disruption of this glymphatic-AQP4 unit is implicated in conditions with altered fluid dynamics, including traumatic brain injury (TBI) and brain tumors. We reviewed experimental and clinical studies examining glymphatic pathways and AQP4 regulation in TBI and brain tumors, and synthesized evidence on glymphatic physiology, AQP4 polarization, and imaging-based assessment to compare mechanisms of disruption in injury versus tumor remodeling. Evidence shows reduced glymphatic transport in both conditions, commonly accompanied by altered AQP4 localization. In TBI, mechanical injury triggers astrocytic reactivity, blood-brain barrier disruption, and loss of perivascular AQP4 polarization, impairing clearance across phases of injury. In brain tumors, parenchymal remodeling, vascular compression, and vasogenic edema disrupt cerebrospinal fluid dynamics and glymphatic pathways. Across disease states, total AQP4 expression alone poorly predicts glymphatic function; instead, spatial localization and polarization of AQP4 at astrocytic endfeet more consistently correlate with clearance efficiency. Emerging imaging approaches, including diffusion-based MRI metrics and perivascular space quantification, offer potential noninvasive methods for assessing glymphatic alterations in vivo, although their reliability and biological specificity remain debated and under active investigation. Overall, the glymphatic-AQP4 system is a key neurovascular interface regulating brain fluid balance. Disrupted AQP4 polarization and glymphatic transport contribute to edema and impaired solute clearance in both TBI and brain tumors. Future work should prioritize standardized imaging biomarkers and time-dependent strategies to restore glymphatic function and perivascular AQP4 organization.