AIMS As a normal physiological process, sleep has recently been shown to facilitate clearance of macromolecular metabolic wastes from the brain via the glymphatic system. The aim of the present study was to investigate pathophysiological roles of astroglial aquaporin 4 (AQP4), a functional regulator of glymphatic clearance, in a mouse model of chronic sleep disruption (SD). METHODS Adult AQP4 null mice and wild-type (WT) mice were given 7 days of SD using the improved rotating rod method, and then received behavioral, neuropathological, and neurochemical analyses. RESULTS Aquaporin 4 deletion resulted in an impairment of glymphatic transport and accumulation of β-amyloid and Tau proteins in the brain following SD. AQP4 null SD mice exhibited severe activation of microglia, neuroinflammation, and synaptic protein loss in the hippocampus, as well as decreased working memory, compared with WT-SD mice. CONCLUSION These results demonstrate that AQP4-mediated glymphatic clearance ameliorates brain impairments caused by abnormal accumulation of metabolic wastes following chronic SD, thus serving as a potential target for sleep-related disorders.

中文翻译：

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水通道蛋白4的缺失加剧了慢性睡眠破坏小鼠模型中的脑损伤。

目的作为一种正常的生理过程，最近发现睡眠有助于通过淋巴系统从大脑清除大分子代谢废物。本研究的目的是调查星形胶质水通道蛋白4（AQP4）的功能，在小鼠慢性睡眠障碍（SD）模型中，其是淋巴清除的功能调节剂。方法采用改良的旋转棒法对成年AQP4无效小鼠和野生型（WT）小鼠进行7天SD，然后进行行为，神经病理学和神经化学分析。结果水通道蛋白4缺失导致SD后脑内的淋巴运输和β-淀粉样蛋白和Tau蛋白的积累受损。AQP4无效SD小鼠在海马中表现出严重的小胶质细胞活化，神经炎症和突触蛋白损失，与WT-SD小鼠相比，还有降低的工作记忆。结论这些结果表明，AQP4介导的淋巴清除率可改善由慢性SD后代谢废物异常蓄积引起的脑损伤，因此可作为睡眠相关疾病的潜在靶标。