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Elife. 2018 Dec 18;7. pii: e40070. doi: 10.7554/eLife.40070.

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

Author information

1
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, United States.
2
Center for Translational Neuromedicine, Faculty of Medical and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Jiangsu Province Key Laboratory of Neurodegeneration, Center for Global Health, Nanjing Medical University, Nanjing, China.
4
RIKEN Center for Brain Science, Wako, Japan.
5
Ochanomizu University, Tokyo, Japan.
6
Gene Therapy Center, The University of North Carolina, Chapel Hill, United States.
7
Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, United States.
8
Advanced Imaging Research Center, Oregon Health and Science University, Portland, United States.
9
Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway.
10
Department of Experimental Medical Science, Lund University, Lund, Sweden.
11
Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden.
12
Department of Pharmacology,School of Medicine, Keio University, Tokyo, Japan.
13
Department of Mechanical Engineering, University of Rochester, Rochester, United States.
14
Department of Physics and Astronomy, University of Rochester, Rochester, United States.
15
Brain and Body System Science Institute, Saitama University, Saitama, Japan.
16
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, North Carolina, United States.
17
Department of Surgery, Duke University School of Medicine, Durham, United States.
18
Knight Cardiovascular Institute, Oregon Health and Science University, Portland, United States.
#
Contributed equally

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 wild-type 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 and shows that glymphatic studies must avoid the use of invasive procedures.

KEYWORDS:

aquaporin-4; cerebrospinal fluid; glymphatic; meta-analysis; mouse; neuroscience; replication study; solute transport

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