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 Na_v1.6 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.

中文翻译：

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AQP4 通过抑制 Nav1.6 介导的星形胶质细胞自噬加重脓毒症相关脑病的认知障碍

脓毒症相关脑病 (SAE) 的病理学与水通道蛋白 4 (AQP4) 相关的星形胶质细胞炎症有关。本文的目的是研究 AQP4 与 SAE 相关的影响，并揭示其导致认知障碍的潜在机制。体内实验结果显示，SAE患者外周血中AQP4表达上调，盲肠结扎穿孔(CLP)小鼠大脑皮质和海马组织中AQP4也明显升高。此外，数据表明，AQP4 缺失可以减轻学习和记忆障碍，归因于星形胶质细胞自噬的激活、星形胶质细胞的失活以及下调 CLP 或脂多糖 (LPS) 诱导的促炎细胞因子的表达。^{此外，AQP4敲除对CLP或LPS诱导的星形胶质细胞PPAR-γ抑制的激活作用与细胞内Ca 2+}水平和钠通道活性有关。SAE 小鼠模型中的学习和记忆障碍可通过激活自噬来减弱 AQP4 敲除，抑制神经炎症，通过下调星形胶质细胞中的 Na _v 1.6 通道来实现神经保护。这导致细胞质中Ca ^{2+积累的减少，进一步激活星形胶质细胞中PPAR-γ信号转导途径的抑制。}