Fig. 1. The brain glymphatic system is a highly organized fluid transport system.

(A) The vascular endfeet of astrocytes create the perivascular spaces through which CSF enters the brain and pervades its interstitium. CSF enters these perivascular spaces from the subarachnoid space, and is propelled by arterial pulsatility deep into the brain, from where CSF enters the neuropil, facilitated by the dense astrocytic expression of the water channel AQP4, which is arrayed in nanoclusters within the endfeet. CSF mixes with fluid in the extracellular space and leaves the brain via the perivenous spaces, as well as along cranial and spinal nerves. Interstitial solutes, including protein waste, are then carried through the glymphatic system and exported from the central nervous system via meningeal and cervical lymphatic vessels. (B) Amyloid-ß plaque formation is associated with an inflammatory response, including reactive micro- and astrogliosis with dispersal of AQP4 nanoclusters. An age-related decline in CSF production, the decrease in perivascular AQP4 polarization, gliosis and plaque formation all impede directional glymphatic flow, and thereby impair waste clearance. Of note, vascular amyloidosis might be initiated by several mechanisms. Amyloid-ß might be taken up from the CSF by vascular smooth muscle cells expressing the low-density lipoprotein receptor-related protein 1 (LRP1) (111). Alternatively, amyloid deposition might be initiated by the backflow of extracellular fluid containing amyloid-ß into the periarterial space from the neuropil – rather than proceeding on to the perivenous spaces - due to an increase in hydrostatic pressure on the venous side, or because of an inflammation-associated loss of AQP4 localization to astrocytic endfeet.