Reviving Brain Waste Clearance: A Pharmacological Perspective on Glymphatic Dysfunction and AQP4 Modulation

The glymphatic system is a brain-wide clearance pathway that maintains CNS homeostasis by eliminating interstitial solutes, including neurotoxic proteins such as amyloid-ß and tau. This process depends on CSF movement through perivascular spaces, where it exchanges with ISF before draining via perivenous routes. Aquaporin-4 (AQP4) fluid channels localized at astrocytic endfeet are central to glymphatic transport, with their polarization being critical for efficiency. Glymphatic activity peaks during sleep but declines with aging, vascular stiffening, and neuroinflammation. Impaired clearance has been linked to the progression of neurodegeneration. Dysregulation of signaling pathways, including NF-kB, Nrf2/keap1, and NLRP3 inflammasome, contributes to AQP4 mislocalization, glial activation, and disrupted fluid dynamics. These alterations promote neuroinflammation and oxidative stress, accelerating neurodegeneration. Pharmacological interventions that restore AQP4 polarization, together with antioxidant and anti-inflammatory therapies, have demonstrated potential in enhancing glymphatic clearance. In addition, recent advances in imaging and drug delivery technologies, such as nanocarriers and non-invasive nose-to-brain systems, provide new opportunities to modulate glymphatic function and improve neuroprotection. However, significant challenges remain in achieving isoform-selective AQP4 modulation, ensuring long-term safety, and translating findings from rodent models to humans. Overall, targeting AQP4 and associated molecular pathways represents a promising adjunctive strategy to enhance waste removal, reduce neuroinflammation, and delay neurodegenerative disease progression.