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

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Abstract

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.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to acknowledge the support provided by Center for Brain Science (The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China) for assistance with experimental facilities.

Funding

This work was supported by programs from the Natural Science Foundation of China (No. 81771168) and Clinical research award of the First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF-CRF-2018–004).

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  1. Ye Yuan and Wei Peng contributed equally.

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  1. Department of Neurology, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Rd, Xi’an, 710061, China

    Ye Yuan, Wei Peng, Jingna Lei, Yi Zhao, Beiyu Zhao, Jin Wang & Qiumin Qu

  2. Center for Brain Science, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Yan Li & Qiumin Qu

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Contributions

All authors contributed to the study conception and design. Ye Yuan, Qiumin Qu, Jin Wang, and Yan Li designed the study; Ye Yuan, Wei Peng, and Jingna Lei performed the research; Ye Yuan, Wei Peng,Yi Zhao, and Beiyu Zhao analyzed data; Ye Yuan wrote the paper. All the authors read and approved the final manuscript.

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All experiments and procedures described in this study were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee at Xi’an Jiaotong University (Xi’an, Shaanxi, China, No. 2019–060). Efforts were made to minimize animal suffering, and all sample sizes for the assessment parameters were calculated to minimize the number of animals used.

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Supplementary file1 (PDF 80541 KB) Fig. S1A. The purity of primary astrocytes. Representative immunofluorescence images of glial fibrillary acidic protein (GFAP) (green) and DAPI (blue) was showed. B Downregulation of AQP4 induced by high-glucose medium. Representative immunoblot bands and densitometric quantification of AQP4 in primary astrocytes cultured in high-glucose medium under 1 day, 3 days and 7 days (n = 3 independent experiments). Data is presented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001; ns, not significant. One-way ANOVA with Tukey’s multiple comparisons test was performed. Scale bars are indicated. Fig.S1C. Representative immunoblot bands and densitometric quantification of AQP4 in primary astrocytes pre-treated with 10umol/l Cycloheximide or DMSO for 6 hours (n = 3 independent experiments). One-way ANOVA with Tukey’s multiple comparisons test was performed. Supplementary Fig. S2 The transfection efficiency of lentivirus. Representative immunofluorescence images of green fluorescent protein (GFP) (green) and bright field image was showed. Supplementary Fig. S3 A: Representative IB bands and densitometric quantification of active-MMP-9 and 43-kDA β-DG in the hippocampus of db/db and wt mice (n=3 per group). B: Representative IB bands and densitometric quantification of active-MMP-9 and 30/43 kDA β-DG in the prefrontal cortex of db/db and wt mice (n=3 per group). C: Representative IB bands and densitometric quantification of MMP-2 (n=3 per group). D: Representative IB bands and densitometric quantification of β-DG in the prefrontal cortex of db/db and wt mice administrated with indicated medicine (n=6 per group). Data is presented as mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001; ns, not significant. Student’s t-test for (A, B) and One-way ANOVA with Tukey’s multiple comparisons test for (C, D)was performed. Scale bars are indicated

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Yuan, Y., Peng, W., Lei, J. et al. AQP4 Endocytosis-Lysosome Degradation Mediated by MMP-9/β-DG Involved in Diabetes Cognitive Impairment. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04085-9

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