Enhanced meningeal lymphatic drainage alleviates cognitive dysfunction induced by anesthesia and surgery in aged mice

Abstract

Postoperative cognitive dysfunction (POCD) occurs in elderly surgical patients as a common complication and manifests as cognitive decline. It is associated with neuroinflammation, microglial activation, and impaired metabolic waste clearance—key mechanisms underlying POCD. Meningeal lymphatic vessels (MLVs) facilitate the drainage of cerebrospinal fluid (CSF) and interstitial fluid (IF), regulating brain immune responses and clearing metabolic waste, immune cells, and antigens, thus modulating neuroinflammation. This study investigates whether enhancing meningeal lymphatic drainage mitigates POCD in aged mice. A POCD mouse model was established via tibial fracture surgery under general anesthesia. Meningeal lymphatic drainage was assessed using immunofluorescence, followed by intra-cisterna magna injection of adeno-associated virus (AAV)-vascular endothelial growth factor-c (AAV-VEGF-C) or AAV-mCherry. Cognitive performance, microglial activation, and pro-inflammatory cytokines were evaluated through behavioral tests, western blotting, and immunofluorescence. Anesthesia and surgery impair the function and morphology of MLVs, leading to reduced lymphatic drainage. These changes were associated with elevated hippocampal expression of microglial activation markers ionized calcium-binding adapter molecule 1 (Iba1) and cluster of differentiation 68 (CD68), as well as increased levels of Interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), which collectively contributed to cognitive impairment. In contrast, AAV-VEGF-C enhanced meningeal lymphatic drainage by promoting lymphangiogenesis and improving function, reduced microglial activation and neuroinflammation, and improved cognitive outcomes. These findings demonstrate that dysfunction of MLVs exacerbates POCD by amplifying neuroinflammation, while enhancing the function of MLVs mitigates these effects. MLVs represent a promising therapeutic target for managing POCD among the aged.