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Aquaporin-4 Deficiency is Associated with Cognitive Impairment and Alterations in astrocyte-neuron Lactate Shuttle

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Abstract

Cognitive impairment refers to notable declines in cognitive abilities including memory, language, and emotional stability leading to the inability to accomplish essential activities of daily living. Astrocytes play an important role in cognitive function, and homeostasis of the astrocyte-neuron lactate shuttle (ANLS) system is essential for maintaining cognitive functions. Aquaporin-4 (AQP-4) is a water channel expressed in astrocytes and has been shown to be associated with various brain disorders, but the direct relationship between learning, memory, and AQP-4 is unclear. We examined the relationship between AQP-4 and cognitive functions related to learning and memory. Mice with genetic deletion of AQP-4 showed significant behavioral and emotional changes including hyperactivity and instability, and impaired cognitive functions such as spatial learning and memory retention. 18 F-FDG PET imaging showed significant metabolic changes in the brains of AQP-4 knockout mice such as reductions in glucose absorption. Such metabolic changes in the brain seemed to be the direct results of changes in the expression of metabolite transporters, as the mRNA levels of multiple glucose and lactate transporters in astrocytes and neurons were significantly decreased in the cortex and hippocampus of AQP-4 knockout mice. Indeed, AQP-4 knockout mice showed significantly higher accumulation of both glucose and lactate in their brains compared with wild-type mice. Our results show that the deficiency of AQP-4 can cause problems in the metabolic function of astrocytes and lead to cognitive impairment, and that the deficiency of AQP4 in astrocyte endfeet can cause abnormalities in the ANLS system.

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Data Availability

All data generated or analyzed during this study are included in this published article and its Additional information files. Further information is available from the corresponding author (rghree@amc.seoul.kr) upon request.

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Acknowledgements

We thank Dr. Eun-Jae Lee for providing the AQP-4 KO mouse. We are also grateful to Dr. Chong Jai Kim for his generous support in equipment and clinical resources. We thank the Metabolomic Core, Positron Emission Tomography core laboratory facilities, the Confocal Microscope Core, and the Laboratory of Animal Research at the ConveRgencemEDIcine research center (CREDIT) at Asan Medical Center for their equipment, services, and expertise.

Funding

This research was supported by a grant from the Korean government Ministry of Science and ICT (MSIT) (2022R1A2C2011941), and 2023IP0037, 2023IP0040 from the Asan Institute for Life sciences, Asan Medical Center (Seoul, Republic of Korea) and KIST Institutional Program(Project No. 2V09540-23-090) to Seungjoo Lee and the Health Fellowship Foundation and the Korean government Ministry of Science and ICT (2022R1C1C2002698) to Hanwool Jeon.

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  1. Hyeuk Cha, June Ho Choi and Hanwool Jeon contributed equally to this work.

Authors and Affiliations

  1. Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea

    Hyeuk Cha, Jun Ho Choi, Hanwool Jeon, Jae Hyun Kim, Moinay Kim, Wonhyoung Park, Eunyeup Lee, Jae Sung Ahn, Jeong Hoon Kim, Seok Ho Hong & Seungjoo Lee

  2. Department of Medical Science, Asan Medical Center, Asan Medical Institute of Convergence Science and Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hyeuk Cha, Eunyeup Lee & Seungjoo Lee

  3. University of Ulsan College of Medicine, Seoul, Republic of Korea

    Wonhyoung Park, Jae Sung Ahn, Jeong Hoon Kim, Seok Ho Hong, Ji Eun Park, Hyun Ju Yoo & Seungjoo Lee

  4. Clinical Research Center, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Joon Seo Lim

  5. Department of Neuroradiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Ji Eun Park

  6. Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea

    Su Jung Kim, Jin Hwa Jung & Hyun Ju Yoo

  7. Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hanwool Jeon & Seungjoo Lee

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Contributions

HC, JHC and HJ performed all experimental procedure and participated to the conceptualization and drafting of the manuscript; JHK, MK, WP, JSL, EL, JSA, JHK, SHH and JEP performed data analysis ; SJK and HJY performed metabolomic analysis on mouse samples; JHJ performed FDG-PET analysis on mouse brain; SL supervised the project and drafted all manuscript. All authors have agreed to the published version of the manuscript.

Corresponding author

Correspondence to Seungjoo Lee.

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This study was approved by the by the Institutional Animal Care and Use Committee (IACUC) at Asan Medical Center (IACUC no.2020-14-156).

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Cha, H., Choi, J.H., Jeon, H. et al. Aquaporin-4 Deficiency is Associated with Cognitive Impairment and Alterations in astrocyte-neuron Lactate Shuttle. Mol Neurobiol 60, 6212–6226 (2023). https://doi.org/10.1007/s12035-023-03475-9

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