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PHARMACOLOGICAL BLOCKADE OF AQUAPORIN-4 INHIBITS GLYMPHATIC FLOW AND CLEARANCE OF TAU FROM THE MOUSE BRAIN

      The glymphatic clearance system is a brain-wide pathway for removal of waste solutes, which depends upon the presence of aquaporin-4 (AQP4) channels, on the endfeet of paravascular astrocytes in the brain (Iliff, et al. (2012)). Glymphatic function has been shown to be impaired in mouse models of Alzheimer’s disease (AD) (Harrison et al., (2016), Peng et al., (2016)), and both amyloid-β (Iliff et al., 2012) and tau (Iliff et al., 2014) have been shown to be cleared from the brain via this system. Until now however, it is unknown whether the glymphatic pathway presents as a suitable drug target. Here we demonstrate that a novel AQP4 inhibitor,TGN-020, suppresses glymphatic function and clearance of tau from the brain, suggesting that pharmacological manipulation of AQP4 function may present as a novel drug target for the treatment of AD.
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