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

  • Brain Behav Immun. 2026 May 8:137:106797. doi: 10.1016/j.bbi.2026.106797.
Han Zhou  1 ,  Lan Mo  2 ,  Wei Tu  3 ,  Binkang Huang  3 ,  Daofan Sun  4 ,  Bo Meng  5 ,  Zhexi Chi  4 ,  Yingying Lv  3 ,  Rongjun Liu  4 ,  Xiuzhong Xing  5 ,  Hui Yuan  5 ,  Jing Yang  4 ,  Junping Chen  6 ,  Xiaowei Chen  7 ,  Bo Lu  8
Affiliations
  • 1. Department of Anesthesiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China; Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China.
  • 2. Department of Anesthesia and Surgery, Hunan Chest Hospital, Changsha, Hunan 410013, China.
  • 3. Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China.
  • 4. Department of Anesthesiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China.
  • 5. Department of Pain, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China.
  • 6. Department of Anesthesiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China. Electronic address: [email protected].
  • 7. Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China. Electronic address: [email protected].
  • 8. Department of Anesthesiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China. Electronic address: [email protected].
PMID: 42107812 DOI: 10.1016/j.bbi.2026.106797
Abstract

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.

Keywords
Aquaporin-4; Glymphatic system; Neuroinflammation; Postoperative cognitive dysfunction.
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