The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future

Abstract

The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed.

Keywords: amyloid-β; aquaporin-4; astrocyte; cerebrospinal fluid; glymphatic; perivascular space.

Figures

Figure 1. Overview of the circulation of CSF and ISF through the glymphatic pathway

The bulk flow of CSF into brain specifically within the perivascular spaces of penetrating arteries drives interstitial metabolic waste products toward perivenous spaces, and ultimately from the cranium via several post-glymphatic clearance sites, including arachnoid granulations, meningeal lymphatic vessels, and along cranial and spinal nerve roots. AQP4 water channels densely expressed within astrocyte end-foot processes circumscribing both arteries and veins act to reduce the resistance to CSF movement from periarterial spaces into the interstitium, and from the interstitium into perivenous spaces. Reproduced with permission from (77).

Figure 2. Post-glymphatic clearance pathways

Glymphatic convective flow is responsible for the drainage of ISF and its constituent solutes, at least in part, to the subarachnoid CSF via perivenous spaces. These solutes can then be cleared to the peripheral venous blood, ultimately to be eliminated in the liver or kidney, by a number of post-glymphatic clearance sites. CSF and waste can pass directly into the venous blood via arachnoid granulations protruding into dural sinuses, such as the superior sagittal sinus (lower left inset). Additionally, macromolecules contained within the CSF can exit the cranium via lymphatic vessels aligning the dural venous sinuses, or alongside olfactory nerves as they traverse the cribiform plate. Both meningeal lymphatics and those positioned within the olfactory mucosa drain to the deep cervical lymph nodes before returning to the venous blood. Reproduced with permission from (78).

Figure 3. Disruption of glymphatic CSF inflow following traumatic brain injury

(A and B) At 1, 3, 7 and 28 days following lateral impact murine ‘Hit & Run’ TBI, mice received a cisterna magna injection (1 μL/min, 10 min) of AlexFluor647-conjugated ovalbumin (45 kDa, 0.5% m/v in artificial CSF). After 30 min of tracer circulation, mice were perfusion fixed and cerebral tissues collected to evaluate glymphatic CSF influx with ex vivo conventional fluorescence microscopy. (C–G) Between 1 and 28 days following TBI there was a significant reduction in glymphatic CSF influx within the hemisphere ipsilateral to the TBI. Interestingly, at 7 days following TBI there was significant global suppression of glymphatic influx with reduced CSF tracer also seen in the contralateral hemisphere. Reproduced with permission from (62).

Figure 4. Impaired glymphatic function after traumatic brain injury is associated with astrocytosis and AQP4 mislocalization

(A) Schematic diagram of lateral impact murine ‘Hit & Run’ TBI. (B and C) At 28 days following TBI there was a significant reactive astrocytosis, as measured by increased GFAP expression, surrounding the lesion core and infiltrating the ipsilateral hemisphere to the impact. (D–F) At the same time point, the astrocytic inflammatory state also resulted in mislocalization of AQP4 water channels away from a perivascular distribution, potentially offering a common mechanism between injury, inflammation and glymphatic failure. Reproduced with permission from (62).