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

Humberto Mestre, Lauren M. Hablitz, Anna L.R. Xavier, Weixi Feng, Wenyan Zou, Tinglin Pu, Hiromu Monai, Giridhar Murlidharan, Ruth M.Castellanos Rivera, Matthew J. Simon, Martin M. Pike, Virginia Plá, Ting Du, Benjamin T. Kress, Xiaowen Wang, Benjamin A. Plog, Alexander S. Thrane, Iben Lundgaard, Yoichiro Abe, Masato YasuiJohn H. Thomas, Ming Xiao, Hajime Hirase, Aravind Asokan, Jeffrey J. Iliff, Maiken Nedergaard

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Article numbere40070
JournaleLife
Volume7
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Mestre, H., Hablitz, L. M., Xavier, A. L. R., Feng, W., Zou, W., Pu, T., Monai, H., Murlidharan, G., Rivera, R. M. C., Simon, M. J., Pike, M. M., Plá, V., Du, T., Kress, B. T., Wang, X., Plog, B. A., Thrane, A. S., Lundgaard, I., Abe, Y., ... Nedergaard, M. (2018). Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife, 7, [e40070]. https://doi.org/10.7554/eLife.40070