AQP4 Endocytosis-Lysosome Degradation Mediated by MMP-9/β-DG Involved in Diabetes Cognitive Impairment

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.