P4‐020: 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. Mice were treated with either AQP4 inhibitor (TGN-020) or vehicle 15mins prior to either, 1) quantification of glymphatic inflow via dynamic contrast-enhanced MRI (intracisternal administration of MRI contrast agent (Gd-DTPA) and concurrent acquisition of whole brain T1-weighted MR images (figure 2a)), or 2) assessment of parenchymal tau clearance (intracerebral infusion of tau-containing brain homogenate and subsequent cerebrospinal fluid collection (figure 2c)). Glymphatic inflow of Gd-DTPA into the parenchyma was significantly ablated after TGN-020 (figure 1 and 2b). Furthermore, intrastriatal infusion of tau-containing brain homogenate revealed that TGN-020 treatment significantly reduced tau clearance from the brain (figure 2d). Comparable TGN-020 induced inhibition of parenchymal inflow of MR contrast agent, and clearance of tau from the brain were observed (table 1), suggestive that TGN-020 inhibits arterial and venous associated AQP4 equally.