Role of AQP4 mediated glymphatic system dysfunction in postoperative neuroinflammation and cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is a common complication in surgical patients, particularly those with pre-existing chronic inflammation. Although impaired glymphatic clearance, a brain waste drainage system dependent on astrocytic aquaporin-4 (AQP4) polarization, is implicated in neurodegenerative disorders, its role in POCD pathogenesis and interaction with neuroinflammation remains unknown. Here, we investigated whetherglymphatic dysfunctiondrives postoperative neuroinflammation and cognitive deficits using a "dual-hit inflammation"model.Our results revealed glymphatic influx/efflux was severely impaired, reaching its lowest point 24 h postoperatively, and gradually recovered by day 7, preceding peak neuroinflammation. AQP4 depolarization correlated with glymphatic dysfunction. Pharmacological AQP4 inhibition (TGN-020)exacerbated glymphatic dysfunction, prolonged cytokine accumulation, and worsened cognitive deficits. HippocampalAQP4 overexpression restored glymphatic clearance, reduced neuroinflammation, and rescued cognition. These findings establish AQP4-mediated glymphatic impairment as an upstream driver of neuroinflammation in POCD, revealing a novel therapeutic target for high-risk surgical patients.