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 Yasui; John H. Thomas; Ming Xiao; Hajime Hirase; Aravind Asokan; Jeffrey J. Iliff; Maiken Nedergaard

doi:10.7554/eLife.40070

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 journal › Article › peer-review

337 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 language	English (US)
Article number	e40070
Journal	eLife
Volume	7
DOIs	https://doi.org/10.7554/eLife.40070
State	Published - Dec 1 2018

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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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, Article e40070. https://doi.org/10.7554/eLife.40070

Mestre, H, Hablitz, LM, Xavier, ALR, Feng, W, Zou, W, Pu, T, Monai, H, Murlidharan, G, Rivera, RMC, Simon, MJ, Pike, MM, Plá, V, Du, T, Kress, BT, Wang, X, Plog, BA, Thrane, AS, Lundgaard, I, Abe, Y, Yasui, M, Thomas, JH, Xiao, M, Hirase, H, Asokan, A, Iliff, JJ & Nedergaard, M 2018, 'Aquaporin-4-dependent glymphatic solute transport in the rodent brain', eLife, vol. 7, e40070. https://doi.org/10.7554/eLife.40070

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title = "Aquaporin-4-dependent glymphatic solute transport in the rodent brain",

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.",

author = "Humberto Mestre and Hablitz, {Lauren M.} and Xavier, {Anna L.R.} and Weixi Feng and Wenyan Zou and Tinglin Pu and Hiromu Monai and Giridhar Murlidharan and Rivera, {Ruth M.Castellanos} and Simon, {Matthew J.} and Pike, {Martin M.} and Virginia Pl{\'a} and Ting Du and Kress, {Benjamin T.} and Xiaowen Wang and Plog, {Benjamin A.} and Thrane, {Alexander S.} and Iben Lundgaard and Yoichiro Abe and Masato Yasui and Thomas, {John H.} and Ming Xiao and Hajime Hirase and Aravind Asokan and Iliff, {Jeffrey J.} and Maiken Nedergaard",

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AU - Mestre, Humberto

AU - Hablitz, Lauren M.

AU - Xavier, Anna L.R.

AU - Feng, Weixi

AU - Zou, Wenyan

AU - Pu, Tinglin

AU - Monai, Hiromu

AU - Murlidharan, Giridhar

AU - Rivera, Ruth M.Castellanos

AU - Simon, Matthew J.

AU - Pike, Martin M.

AU - Plá, Virginia

AU - Du, Ting

AU - Kress, Benjamin T.

AU - Wang, Xiaowen

AU - Plog, Benjamin A.

AU - Thrane, Alexander S.

AU - Lundgaard, Iben

AU - Abe, Yoichiro

AU - Yasui, Masato

AU - Thomas, John H.

AU - Xiao, Ming

AU - Hirase, Hajime

AU - Asokan, Aravind

AU - Iliff, Jeffrey J.

AU - Nedergaard, Maiken

PY - 2018/12/1

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N2 - 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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Aquaporin-4-dependent glymphatic solute transport in the rodent brain

Abstract

ASJC Scopus subject areas

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