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

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

doi:10.7554/elife.40070

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.

Highlights

A brain-wide fluid transport pathway, known as the glymphatic system, supports the rapid exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) along perivascular pathways (Iliff et al, 2012)
Quantification of the mean integrated optical density (MIOD) of TRd3 on the dorsal and ventral brain surface along anterior-posterior position of bregma showed a significant reduction in Aqp4 KO mice compared with wild type (WT) mice (Figure 2a–c)
This study evaluated the role of the astrocytic water channel AQP4 in the dispersion of fluorescent tracers or contrast agents by five independent groups

Summary

Introduction

A brain-wide fluid transport pathway, known as the glymphatic system, supports the rapid exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) along perivascular pathways (Iliff et al, 2012). Astrocytic endfeet ensheath the cerebral vasculature, and the abundantly expressed astroglial water channel aquaporin-4 (AQP4) localizes primarily to the perivascular endfoot membrane domain abutting the basal lamina As this anatomic arrangement provides a route for rapid water movement between the perivascular space and the glial syncytium, AQP4 has been proposed to support perivascular fluid and solute movement along the glymphatic system (Nedergaard, 2013). The critical role of AQP4 in supporting perivascular CSF-ISF exchange was recently questioned in a report by Smith et al (2017), in which the authors failed to detect any reduction in CSF tracer influx into the brain parenchyma of Aqp KO mice compared to wild-type (WT) controls. Interstitial fluid transport should not be studied following invasive procedures in the brain

Results

Discussion

Materials and methods

Funding Funder