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

Mestre H, Hablitz LM, Xavier AL, Feng W, Zou W, Pu T, Monai H, Murlidharan G, Castellanos Rivera RM, 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
eLife 2018
Open on PubMed

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.

8 Figures Extracted
Figure 1.
Figure 1. PMC
Strategy used for generation of KO mice and the experimental design of the study. Top row of each panel represents the institution where the line orig...
Figure 2.
Figure 2. PMC
NMU: Aqp4 gene deletion reduced the penetration of intracisternally injected tracer into the brain parenchyma. Texas Red-conjugated dextran (TRd3, 3...
Figure 3.
Figure 3. PMC
RIKEN: Aqp4 -/- mice display compromised CSF tracer infiltration under ketamine-xylazine anesthesia. ( a ) Schematic diagram for CM injection of BD...
Figure 4.
Figure 4. PMC
UNC: CSF tracer influx is decreased in Aqp4 KO mice. ( a ) Coronal sections from a C57BL/6 wild-type mouse (WT), CD1 background strain control ( Aqp...
Figure 5.
Figure 5. PMC
URMC: Glymphatic influx of CSF tracer is facilitated by AQP4. ( a ) Representative images from an in vivo transcranial optical imaging experiment of a...
Figure 6.
Figure 6. PMC
Deletion of the adapter protein α-syntrophin impairs AQP4 perivascular localization, and CSF influx into the brain parenchyma. Dynamic contrast enhanc...
Figure 7.
Figure 7. PMC
A unilateral intrastriatal injection reduces global glymphatic function. ( a ) KX-anesthesized mice received an injection into striatum. After injecti...
Figure 8.
Figure 8. PMC
Evidence evaluating the role of AQP4 in CSF influx and ISF efflux. ( a ) Meta-analysis from experiments that delivered either fluorescence- or radio-l...
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