Chronic stress impairs the aquaporin-4-mediated glymphatic transport through glucocorticoid signaling
Chronic stress impairs the aquaporin-4-mediated glymphatic transport through glucocorticoid signaling
复制标题
慢性应激通过糖皮质激素信号传导损害水通道蛋白 4 介导的类淋巴运输
DOI：
10.1007/s00213-018-5147-6
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发表时间：
2019-04-01
影响因子：
3.4
通讯作者：
Wang, Lin-Hui
中科院分区：
文献类型：
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作者：
Wei, Fang;Song, Jian;Wang, Lin-Hui
背景胶质淋巴系统最近被认为是一个脑内的宏观系统，用于清除潜在的有害分子，如β淀粉样蛋白（例如，A），来自脑实质。先前的文献已经确定胶质淋巴功能受到衰老、创伤性脑损伤和一些疾病的显著抑制。然而，慢性应激对胶质淋巴功能的影响及其潜在机制在很大程度上仍是未知的。方法成年小鼠随机分为4组：慢性不可预测的轻度应激（CIMTS）治疗组，CIMTS同时与米非司酮（MFP）组，地塞米松（DEX）治疗组，对照组。通过体重变化、血浆皮质酮水平和行为测试观察应激反应。ELISA法检测脑组织中A42的含量。用荧光示踪剂注射法测定胶质淋巴功能。采用免疫组化和western blot检测水通道蛋白4（AQP4）的表达和定位。结果与对照组相比，实验组小鼠整体胶质淋巴功能受损，尤其是前脑胶质淋巴功能受损。这种变化伴随着AQP4的表达和极化减少，AQP4，聚集蛋白，层粘连蛋白和肌营养不良蛋白聚糖在前皮质的转录减少。同样，糖皮质激素受体（GR）激动剂DEX暴露可降低胶质淋巴功能和AQP4表达。结论慢性应激可通过糖皮质激素信号通路损害AQP4介导的胶质淋巴转运功能。我们的研究结果还表明，GR拮抗剂可能有助于挽救慢性应激抑制的胶质淋巴功能。
BackgroundThe glymphatic system has recently been proposed to function as a brain-wide macroscopic system for the clearance of potentially harmful molecules, such as amyloid beta (e.g., A), from the brain parenchyma. Previous literatures have established that the glymphatic function is dramatically suppressed by aging, traumatic brain injury, and some diseases. However, the effect of chronic stress on the glymphatic function and its underlying mechanism remains largely unknown.MethodsAdult mice were randomly divided into four groups: chronic unpredictable mild stress (CUMS)-treated group, CUMS simultaneously treated with mifepristone (MFP) group, dexamethasone (DEX)-treated group, and control group. Stress response was observed by assessing the change of body weight, plasma corticosterone level, and behavior tests. The level of A42 in cerebral tissue was assessed by ELISA. The glymphatic function was determined by using fluorescence tracer injection. The expression and localization of aquaporin-4 (AQP4) were evaluated by immunohistochemistry and western blot. The transcription level of AQP4 and anchoring molecules was evaluated by real-time PCR.FindingsCompared with control group, CUMS-treated mice exhibited the impairment of global glymphatic function especially in the anterior brain. This change was accompanied by the decreased expression and polarization of AQP4, reduced transcription of AQP4, agrin, laminin, and dystroglycan in the anterior cortex. Similarly, the glucocorticoid receptor (GR) agonist DEX exposure could reduce the glymphatic function and AQP4 expression. Moreover, the GR antagonist MFP treatment could significantly rescue the glymphatic function and reverse the expression and polarization of AQP4 impaired by CUMS.ConclusionChronic stress could impair the AQP4-mediated glymphatic transport in the brain through glucocorticoid signaling. Our results also suggest that GR antagonist could be beneficial to rescue the glymphatic function suppressed by chronic stress.