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

Mestre, Humberto; Hablitz, Lauren M.; Xavier, Anna Lr; Feng, Weixi; Zou, Wenyan; Pu, Tinglin; Monai, Hiromu; Murlidharan, Giridhar; Castellanos Rivera, Ruth M. and Simon, Matthew J., et al. (2018) In eLife 7.
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.... (More)

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.

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@article{6daff63e-0a6f-4bf3-a078-2f463b7ba944,
  abstract     = {<p>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.</p>},
  articleno    = {e40070},
  author       = {Mestre, Humberto and Hablitz, Lauren M. and Xavier, Anna Lr and Feng, Weixi and Zou, Wenyan and Pu, Tinglin and Monai, Hiromu and Murlidharan, Giridhar and Castellanos Rivera, Ruth M. and Simon, Matthew J. and Pike, Martin M. and Plá, Virginia and Du, Ting and Kress, Benjamin T. and Wang, Xiaowen and Plog, Benjamin A. and Thrane, Alexander S. and Lundgaard, Iben and Abe, Yoichiro and Yasui, Masato and Thomas, John H. and Xiao, Ming and Hirase, Hajime and Asokan, Aravind and Iliff, Jeffrey J. and Nedergaard, Maiken},
  issn         = {2050-084X},
  keyword      = {aquaporin-4,cerebrospinal fluid,glymphatic,meta-analysis,mouse,neuroscience,replication study,solute transport},
  language     = {eng},
  month        = {12},
  publisher    = {eLife Sciences Publications LTD.},
  series       = {eLife},
  title        = {Aquaporin-4-dependent glymphatic solute transport in the rodent brain},
  url          = {http://dx.doi.org/10.7554/eLife.40070},
  volume       = {7},
  year         = {2018},
}