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Mechanism of depression as a risk factor in the development of Alzheimer’s disease: the function of AQP4 and the glymphatic system

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Abstract

Background

Many studies have indicated that a history of depression increases the risk of developing Alzheimer’s disease (AD); however, the potential pathogenestic mechanism by which depression functions as a high risk factor for AD remains unknown. Recently, a “cerebral lymphatic system” referred to as “glymphatic system” has been demonstrated to be responsible for neuronal extracellular waste protein clearance via a paravascular pathway. However, the function of glymphatic pathway has not been determined in depressive disorders.

Methods

The present study used an animal model of chronic unpredictable mild stress (CUMS) to determine the function of glymphatic pathway by using fluorescence tracers. Immunohistochemistry was used to assess the accumulation of endogenous mouse and exogenous human amyloid beta 42 (Aβ42) in CUMS-treated mice with or without treatment with antidepressant fluoxetine.

Findings

Glymphatic pathway circulation was impaired in mice treated with CUMS; moreover, glymphatic pathway dysfunction suppressed Aβ42 metabolism, because the accumulation of endogenous and exogenous Aβ42 was increased in the brains of the CUMS-treated mice. However, treatment with fluoxetine reversed these destructive effects of CUMS on glymphatic system. In anhedonic mice, the expression of the water channel aquaporin 4 (AQP4), a factor in glymphatic pathway dysfunction, was down-regulated in cortex and hippocampus.

Conclusion

The dysfunction of glymphatic system suggested why a history of depression may be a strong risk factor for AD in anhedonic mice. We hope our study will contribute to an understanding of the risk mechanism of depressive disorder in the development of AD and the mechanisms of antidepressant therapies in AD.

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Acknowledgements

This study was supported by grant no. 81200935 to MX from the National Natural Science Foundation of China, grant no. 20102104120002 to MX from the Doctoral Fund of Education Ministry of China, grant no. L2011135 to MX from the Educational Commission of Liaoning Province of China, grant no. 201602834 to BL from the Natural Science Foundation of Liaoning Province and grant no. [2015]1098 to BL from the Scientific Research Foundation for Overseas Scholars of Education Ministry of China.

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Authors and Affiliations

  1. Laboratory of Brain Metabolic Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, No. 77, Puhe Street, Shenbei District, Shenyang, 110177, People’s Republic of China

    Maosheng Xia, Li Yang, Guangfeng Sun, Shuang Qi & Baoman Li

  2. Department of Orthopaedics, The First Hospital of China Medical University, Shenyang, People’s Republic of China

    Maosheng Xia, Guangfeng Sun, Shuang Qi & Baoman Li

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  1. Maosheng Xia
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  2. Li Yang
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  3. Guangfeng Sun
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  5. Baoman Li
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Correspondence to Baoman Li.

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Xia, M., Yang, L., Sun, G. et al. Mechanism of depression as a risk factor in the development of Alzheimer’s disease: the function of AQP4 and the glymphatic system. Psychopharmacology 234, 365–379 (2017). https://doi.org/10.1007/s00213-016-4473-9

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