Department of Physiology and Neurobiology, Medical College of Soochow University, 199 Ren-Ai Road, Suzhou, 215123, People's Republic of China.
Department of Orthopaedics, The first affiliated hospital of Soochow University, 188 Shi-Zi Street, Suzhou, 215006, People's Republic of China.
Psychopharmacology (Berl). 2019 Apr;236(4):1367-1384. doi: 10.1007/s00213-018-5147-6. Epub 2019 Jan 3.
The 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., Aβ), 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.
Adult 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 Aβ42 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.
Compared 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.
Chronic 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.
最近提出了糖质系统作为大脑中清除潜在有害物质（如淀粉样蛋白β（例如，Aβ））的宏观系统。先前的文献已经证实，糖质系统功能随着年龄的增长、创伤性脑损伤和某些疾病而明显受到抑制。然而，慢性应激对糖质系统功能的影响及其潜在机制在很大程度上仍不清楚。
成年小鼠被随机分为四组：慢性不可预测轻度应激（CUMS）处理组、CUMS 同时给予米非司酮（MFP）组、地塞米松（DEX）处理组和对照组。通过评估体重、血浆皮质酮水平和行为测试来观察应激反应。通过 ELISA 评估脑组织中 Aβ42 的水平。通过荧光示踪剂注射来确定糖质系统功能。通过免疫组织化学和 Western blot 评估水通道蛋白-4（AQP4）的表达和定位。通过实时 PCR 评估 AQP4 和锚定分子的转录水平。
与对照组相比，CUMS 处理组的整体糖质系统功能受损，尤其是在前脑。这种变化伴随着 AQP4 的表达和极化减少，前皮质的 AQP4、神经节苷脂、层粘连蛋白和 dystroglycan 的转录减少。同样，糖皮质激素受体（GR）激动剂 DEX 暴露会降低糖质系统功能和 AQP4 表达。此外，GR 拮抗剂 MFP 处理可显著挽救 CUMS 引起的糖质系统功能障碍和逆转 AQP4 的表达和极化。
慢性应激可通过糖皮质激素信号损害大脑中的 AQP4 介导的糖质转运。我们的结果还表明，GR 拮抗剂可能有益于挽救慢性应激抑制的糖质系统功能。
