Cognitive impairment is considered to be one of the important comorbidities of diabetes, but the underlying mechanisms are widely unknown. Aquaporin-4 (AQP4) is the most abundant water channel in the central nervous system, which plays a neuroprotective role in various neurological diseases by maintaining the function of glymphatic system and synaptic plasticity. However, whether AQP4 is involved in diabetes-related cognitive impairment remains unknown. β-dystroglycan (β-DG), a key molecule for anchoring AQP4 on the plasma membrane of astrocytes and avoiding its targeting to lysosomes for degradation, can be cleaved by matrix metalloproteinase-9 (MMP-9). β-DG deficiency can cause a decline in AQP4 via regulating its endocytosis. However, whether cleavage of β-DG can affect the expression of AQP4 remains unreported. In this study, we observed that diabetes mice displayed cognitive disorder accompanied by reduction of AQP4 in prefrontal cortex. And we found that bafilomycin A1, a widely used lysosome inhibitor, could reverse the downregulation of AQP4 in diabetes, further demonstrating that the reduction of AQP4 in diabetes is a result of more endocytosis-lysosome degradation. In further experiments, we found diabetes caused the excessive activation of MMP-9/β-DG which leaded to the loss of connection between AQP4 and β-DG, further inducing the endocytosis of AQP4. Moreover, inhibition of MMP-9/β-DG restored the endocytosis-lysosome degradation of AQP4 and partially alleviated cognitive dysfunction in diabetes. Our study sheds new light on the role of AQP4 in diabetes-associated cognitive disorder. And we provide a promising therapeutic target to reverse the endocytosis-lysosome degradation of AQP4 in diabetes, such as MMP-9/β-DG.

认知障碍被认为是糖尿病的重要合并症之一，但其潜在机制尚不清楚。水通道蛋白-4（AQP4）是中枢神经系统中最丰富的水通道，通过维持类淋巴系统功能和突触可塑性，在多种神经系统疾病中发挥神经保护作用。然而，AQP4 是否参与糖尿病相关的认知障碍仍不清楚。 β-肌营养不良聚糖 (β-DG) 是将 AQP4 锚定在星形胶质细胞质膜上并避免其靶向溶酶体降解的关键分子，可以被基质金属蛋白酶 9 (MMP-9) 裂解。 β-DG 缺乏可通过调节 AQP4 的内吞作用导致 AQP4 下降。然而，β-DG的裂解是否会影响AQP4的表达尚未见报道。在这项研究中，我们观察到糖尿病小鼠表现出认知障碍，并伴有前额皮质 AQP4 的减少。我们发现广泛使用的溶酶体抑制剂巴弗洛霉素A1可以逆转糖尿病中AQP4的下调，进一步证明糖尿病中AQP4的降低是更多内吞作用-溶酶体降解的结果。在进一步的实验中，我们发现糖尿病引起MMP-9/β-DG的过度激活，导致AQP4和β-DG之间的连接丧失，进一步诱导AQP4的内吞作用。此外，抑制 MMP-9/β-DG 可恢复 AQP4 的内吞作用-溶酶体降解，并部分缓解糖尿病的认知功能障碍。我们的研究为 AQP4 在糖尿病相关认知障碍中的作用提供了新的线索。我们提供了一个有前景的治疗靶点来逆转糖尿病中 AQP4 的内吞作用-溶酶体降解，例如 MMP-9/β-DG。