Glymphatic System: Emerging Therapeutic Target for Neurological Diseases

Abstract

The newly discovered glymphatic system acts as pseudolymphatic vessels subserving brain waste clearance and is functionally dependent on astrocytic aquaporin-4 channels. The glymphatic system primarily functions during sleep as an interchange between cerebrospinal fluid and interstitial fluid, with cerebrospinal fluid flowing into the parenchyma via the perivascular spaces and then exchanging with interstitial fluid. The discovery of meningeal lymphatics helps refine the conceptual framework of glymphatic pathway, as certain waste products collected alongside perivascular spaces ultimately drain into the cervical lymph nodes via meningeal lymphatics, whose function regulates the functioning of the glymphatic system. The glymphatic and meningeal lymphatic systems are critical for the homeostasis of central nervous system, and their malfunctions complicate cerebral dysfunction and diseases. The present review will shed light on the structure, regulation, functions, and interrelationships of the glymphatic system and meningeal lymphatics. We will also expound on their impairments and corresponding targeted intervention in neurodegenerative diseases, traumatic brain injury, stroke, and infectious/autoimmune diseases, offering valuable references for future research.

Figure 1

The glymphatic system functions as an interchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF) and facilitates their exchange to promote waste removal. CSF within the subarachnoid space flows into the parenchyma via the periarterial space and subsequently exchanges with ISF, which is facilitated by astrocytic aquaporin-4 and drives the convective flow of interstitial solutes and ISF into perivenous spaces. Eventually, mixed CSF, ISF, and interstitial solutes flow along the perivenous space to remove metabolic waste products away from the brain parenchyma.

Figure 2

Schematic diagram of the circulation of cerebrospinal fluid (CSF) in the brain. CSF secreted by the choroid plexus flows into the subarachnoid space through the apertures of Magendie and Luschka of the fourth ventricle and then enters the perivascular spaces (glymphatic system). CSF collected alongside perivascular spaces ultimately drains into the periphery through meningeal lymphatics, arachnoid villi, the cribriform plate, and the spinal nerve root.