Aquaporin-4-dependent glymphatic solute transport in the rodent brain
- University of Rochester Medical Center, United States
- University of Copenhagen, Denmark
- Nanjing Medical University, China
- RIKEN, Japan
- The University of North Carolina at Chapel Hill, United States
- Oregon Health and Science University, United States
- Haukeland University Hospital, Norway
- Lund University, Sweden
- Keio University, Japan
- 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
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.
Reviewing Editor
- David Kleinfeld, University of California, San Diego, United States
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.
Version history
- Received: July 20, 2018
- Accepted: December 17, 2018
- Accepted Manuscript published: December 18, 2018 (version 1)
- Accepted Manuscript updated: December 19, 2018 (version 2)
- Version of Record published: December 27, 2018 (version 3)
- 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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Aquaporin-4-dependent glymphatic solute transport in the rodent brain
eLife 7:e40070.
https://doi.org/10.7554/eLife.40070
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