Aquaporin-4-dependent glymphatic solute transport in the rodent brain

  1. Humberto Mestre  Is a corresponding author
  2. Lauren M Hablitz
  3. Anna LR Xavier
  4. Weixi Feng
  5. Wenyan Zou
  6. Tinglin Pu
  7. Hiromu Monai
  8. Giridhar Murlidharan
  9. Ruth M Castellanos Rivera
  10. Matthew J Simon
  11. Martin M Pike
  12. Virginia Plá
  13. Ting Du
  14. Benjamin T Kress
  15. Xiaowen Wang
  16. Benjamin A Plog
  17. Alexander S Thrane
  18. Iben Lundgaard
  19. Yoichiro Abe
  20. Masato Yasui
  21. John H Thomas
  22. Ming Xiao  Is a corresponding author
  23. Hajime Hirase  Is a corresponding author
  24. Aravind Asokan  Is a corresponding author
  25. Jeffrey J Iliff  Is a corresponding author
  26. Maiken Nedergaard  Is a corresponding author
  1. University of Rochester Medical Center, United States
  2. University of Copenhagen, Denmark
  3. Nanjing Medical University, China
  4. RIKEN, Japan
  5. The University of North Carolina at Chapel Hill, United States
  6. Oregon Health and Science University, United States
  7. Haukeland University Hospital, Norway
  8. Lund University, Sweden
  9. Keio University, Japan
  10. University of Rochester, United States

Abstract

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid(CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4(AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out(KO) on CSF and interstitial fluid(ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wildtype mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4(Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 in accordance with the glymphatic system and shows that invasive procedures should not be utilized.

Data availability

All data generated or analysed during this study are included in the manuscript.

Article and author information

Author details

  1. Humberto Mestre

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    For correspondence
    humberto_mestre@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5876-5397
  2. Lauren M Hablitz

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Anna LR Xavier

    Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  4. Weixi Feng

    Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Wenyan Zou

    Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Tinglin Pu

    Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Hiromu Monai

    Center for Brain Science, RIKEN, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  8. Giridhar Murlidharan

    Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ruth M Castellanos Rivera

    Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Matthew J Simon

    Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Martin M Pike

    Advanced Imaging Research Center, Oregon Health and Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Virginia Plá

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Ting Du

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Benjamin T Kress

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Xiaowen Wang

    Center for Brain Science, RIKEN, Wako, Japan
    Competing interests
    The authors declare that no competing interests exist.
  16. Benjamin A Plog

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Alexander S Thrane

    Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway
    Competing interests
    The authors declare that no competing interests exist.
  18. Iben Lundgaard

    Department of Experimental Medical Science, Lund University, Lund, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  19. Yoichiro Abe

    Department of Pharmacology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6163-8794
  20. Masato Yasui

    Department of Pharmacology, Keio University, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  21. John H Thomas

    Department of Mechanical Engineering, University of Rochester, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Ming Xiao

    Jiangsu Province Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China
    For correspondence
    mingx@njmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  23. Hajime Hirase

    Center for Brain Science, RIKEN, Wako, Japan
    For correspondence
    hajime.hirase@riken.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3806-6905
  24. Aravind Asokan

    Gene Therapy Center, The University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    aravind_asokan@med.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
  25. Jeffrey J Iliff

    Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, United States
    For correspondence
    iliffj@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
  26. Maiken Nedergaard

    Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States
    For correspondence
    maiken_nedergaard@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (NS100366)

  • Maiken Nedergaard

Japan Society for the Promotion of Science (18H02606)

  • Masato Yasui

Human Frontier Science Program (RGP0036/2014)

  • Hajime Hirase

Japan Society for the Promotion of Science (Core-to-Core Program)

  • Hajime Hirase

Lundbeckfonden (Visiting Professorship)

  • Hajime Hirase

Knut och Alice Wallenbergs Stiftelse (Helse Vet)

  • Alexander S Thrane

National Institutes of Health (NS061800)

  • Aravind Asokan

National Institutes of Health (AG048769)

  • Maiken Nedergaard

National Institutes of Health (AG054456)

  • Jeffrey J Iliff

National Institutes of Health (NS099371)

  • Aravind Asokan

National Institutes of Health (HL089221)

  • Aravind Asokan

National Institutes of Health (NS089709)

  • Jeffrey J Iliff

National Institutes of Health (NS078394)

  • Maiken Nedergaard

National Institutes of Health (AG048769)

  • Maiken Nedergaard

Japan Society for the Promotion of Science (18K14859)

  • Hiromu Monai

Japan Society for the Promotion of Science (16H01888)

  • Hajime Hirase

Japan Society for the Promotion of Science (18H05150)

  • Hajime Hirase

Japan Society for the Promotion of Science (17K19637)

  • Yoichiro Abe

Japan Society for the Promotion of Science (16H05134)

  • Yoichiro Abe

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC-1601106), Wako Animal Experiment Committee, RIKEN (Recombinant DNA experimentation protocol: 2016-038; Animal experimentation protocol: H29-2-227), The University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee (protocol 15-109), the University Committee on Animal Resources of the University of Rochester (protocol 2011-023), and the IACUC of Oregon Health and Science University (protocol IP00000394). All experiments were performed in accordance with the approved guidelines and regulations. All efforts were made to minimize animal suffering and to reduce the number of animals used for the experiments.

Reviewing Editor

  1. David Kleinfeld, University of California, San Diego, United States

Publication history

  1. Received: July 20, 2018
  2. Accepted: December 17, 2018
  3. Accepted Manuscript published: December 18, 2018 (version 1)
  4. Accepted Manuscript updated: December 19, 2018 (version 2)
  5. Version of Record published: December 27, 2018 (version 3)
  6. Version of Record updated: December 28, 2018 (version 4)

Copyright

© 2018, Mestre et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Humberto Mestre
  2. Lauren M Hablitz
  3. Anna LR Xavier
  4. Weixi Feng
  5. Wenyan Zou
  6. Tinglin Pu
  7. Hiromu Monai
  8. Giridhar Murlidharan
  9. Ruth M Castellanos Rivera
  10. Matthew J Simon
  11. Martin M Pike
  12. Virginia Plá
  13. Ting Du
  14. Benjamin T Kress
  15. Xiaowen Wang
  16. Benjamin A Plog
  17. Alexander S Thrane
  18. Iben Lundgaard
  19. Yoichiro Abe
  20. Masato Yasui
  21. John H Thomas
  22. Ming Xiao
  23. Hajime Hirase
  24. Aravind Asokan
  25. Jeffrey J Iliff
  26. Maiken Nedergaard
(2018)
Aquaporin-4-dependent glymphatic solute transport in the rodent brain
eLife 7:e40070.
https://doi.org/10.7554/eLife.40070
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