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

Han Zhou; Lan Mo; Wei Tu; Binkang Huang; Daofan Sun; Bo Meng; Zhexi Chi; Yingying Lv; Rongjun Liu; Xiuzhong Xing; Hui Yuan; Jing Yang; Junping Chen; Xiaowei Chen; Bo Lu

doi:10.1016/j.bbi.2026.106797

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. Online ahead of print.

Authors

Han Zhou¹, Lan Mo², Wei Tu³, Binkang Huang³, Daofan Sun⁴, Bo Meng⁵, Zhexi Chi⁴, Yingying Lv³, Rongjun Liu⁴, Xiuzhong Xing⁵, Hui Yuan⁵, Jing Yang⁴, Junping Chen⁶, Xiaowei Chen⁷, Bo Lu⁸

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: 13858222873@163.com.
⁷ Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, China. Electronic address: chenxiaowei@nbu.edu.cn.
⁸ Department of Anesthesiology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, China. Electronic address: nblbmz@hotmail.com.

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.