AQP4 Aggravates Cognitive Impairment in Sepsis‐Associated Encephalopathy through Inhibiting Nav1.6‐Mediated Astrocyte Autophagy

• Published in: Advanced science Vol. 10; no. 14
• Main Authors: Zhu, Dan‐Dan, Huang, Yue‐Lin, Guo, Song‐Yu, Li, Na, Yang, Xue‐Wei, Sui, Ao‐Ran, Wu, Qiong, Zhang, Yue, Kong, Yue, Li, Qi‐Fa, Zhang, Ting, Zheng, Wen‐Fei, Li, Ai‐Ping, Yu, Jian, Ma, Tong‐Hui, Li, Shao
• Format: Journal Article
• Language: English
• Published: Weinheim John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc; Wiley
• Subjects: Alzheimer's disease; AQP4; astrocyte; Autophagy; Biomarkers; Cytokines; Health care; Mortality; Nervous system; neuroinflammation; Neurons; Patients; Proteins; Sepsis; sepsis‐associated encephalopathy; sodium channel Nav1.6; Traumatic brain injury; Tumor necrosis factor-TNF
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202205862

The pathology of sepsis‐associated encephalopathy (SAE) is related to astrocyte‐inflammation associated with aquaporin‐4 (AQP4). The aim here is to investigate the effects of AQP4 associated with SAE and reveal its underlying mechanism causing cognitive impairment. The in vivo experimental results reveal that AQP4 in peripheral blood of patients with SAE is up‐regulated, also the cortical and hippocampal tissue of cecal ligation and perforation (CLP) mouse brain has significant rise in AQP4. Furthermore, the data suggest that AQP4 deletion could attenuate learning and memory impairment, attributing to activation of astrocytic autophagy, inactivation of astrocyte and downregulate the expression of proinflammatory cytokines induced by CLP or lipopolysaccharide (LPS). Furthermore, the activation effect of AQP4 knockout on CLP or LPS‐induced PPAR‐γ inhibiting in astrocyte is related to intracellular Ca2+ level and sodium channel activity. Learning and memory impairment in SAE mouse model are attenuated by AQP4 knockout through activating autophagy, inhibiting neuroinflammation leading to neuroprotection via down‐regulation of Nav1.6 channels in the astrocytes. This results in the reduction of Ca2+ accumulation in the cell cytosol furthermore activating the inhibition of PPAR‐γ signal transduction pathway in astrocytes. SAE mouse model is constructed by cecal ligation and perforation for in vivo experiments and consequent electrophysiology, behavior, and molecular analysis. Primary astrocytes are cultured and stimulated by using lipopolysaccharide (LPS) for in vitro analysis. The pictographic flowchart theorizes that AQP4 aggravates sepsis‐induced neuronal injury and cognitive dysfunction by inhibiting autophagy and activating an inflammatory response in astrocytes.