A real-time in vivo clearance assay for quantification of glymphatic efflux

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Glymphatic fluid transport eliminates metabolic waste from the brain including amyloid-β, yet the methodology for studying efflux remains rudimentary. Here, we develop a method to evaluate glymphatic real-time clearance. Efflux of Direct Blue 53 (DB53, also T-1824 or Evans Blue) injected into the striatum is quantified by imaging the DB53 signal in the vascular compartment, where it is retained due to its high affinity to albumin. The DB53 signal is detectable as early as 15 min after injection and the efflux kinetics are sharply reduced in mice lacking the water channel aquaporin 4 (AQP4). Pharmacokinetic modeling reveal that DB53 efflux is consistent with the existence of two efflux paths, one with fast kinetics (T1/2 = 50 min) and another with slow kinetics (T1/2 = 240 min), in wild-type mice. This in vivo methodology will aid in defining the physiological variables that drive efflux, as well as the impact of brain states or disorders on clearance kinetics.
OriginalsprogEngelsk
Artikelnummer111320
TidsskriftCell Reports
Vol/bind40
Udgave nummer11
Antal sider20
ISSN2211-1247
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
We thank Dan Xue for expert graphical support. This project has received funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation , the NIH/NINDS/NIA ( R01NS100366 , RF1AG057575 ), the Novo Nordisk and the Lundbeck Foundation , as well as by the US Army Research Office (grant MURI W911NF1910280). The views and conclusions contained in this review are solely those of the authors and should not be interpreted as representing the policies, either expressed or implied, of the sponsors, the National Institutes of Health , the Army Research Office , or the US Government . The US Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein.

Funding Information:
We thank Dan Xue for expert graphical support. This project has received funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the NIH/NINDS/NIA (R01NS100366, RF1AG057575), the Novo Nordisk and the Lundbeck Foundation, as well as by the US Army Research Office (grant MURI W911NF1910280). The views and conclusions contained in this review are solely those of the authors and should not be interpreted as representing the policies, either expressed or implied, of the sponsors, the National Institutes of Health, the Army Research Office, or the US Government. The US Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein. V.P. and M.N. conceived the experimental design. V.P. G.O. A.H. A.L.-d.-G. M.J.G. and L.M.H. provided data collection. V.P. G.O. A.H. and A.L.-d.-G. performed data analysis. V.P. carried out figure preparation. P.B. and D.H.K. carried out pharmacokinetic modeling. V.P. L.M.H. and M.N. contributed to manuscript writing and preparation. R.H. and W.W. provided resources and unpublished data. All authors read and approved the final version of this manuscript. The authors declare no competing interests.

Publisher Copyright:
© 2022

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