The meningeal lymphatic vessels and the glymphatic system: Potential therapeutic targets in neurological disorders

Abstract

The recent discovery of the meningeal lymphatic vessels (mLVs) and glymphatic pathways has challenged the long-lasting dogma that the central nervous system (CNS) lacks a lymphatic system and therefore does not interact with peripheral immunity. This discovery has reshaped our understanding of mechanisms underlying CNS drainage. Under normal conditions, a close connection between mLVs and the glymphatic system enables metabolic waste removal, immune cell trafficking, and CNS immune surveillance. Dysfunction of the glymphatic-mLV system can lead to toxic protein accumulation in the brain, and it contributes to the development of a series of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. The identification of precise cerebral transport routes is based mainly on indirect, invasive imaging of animals, and the results cannot always be applied to humans. Here we review the functions of the glymphatic-mLV system and evidence for its involvement in some CNS diseases. We focus on emerging noninvasive imaging techniques to evaluate the human glymphatic-mLV system and their potential for preclinical diagnosis and prevention of neurodegenerative diseases. Potential strategies that target the glymphatic-mLV system in order to treat and prevent neurological disorders are also discussed.

Keywords: CNS diseases; brain clearance system; glymphatic pathways; mLVs; meningeal immunity.

Figure 1.

Schematic representation of the glymphatic pathway. A functional glymphatic pathway consists of three consecutive components: (1) afferent perfusion of CSF into the parenchyma along the para-arterial space, (2) mixing and exchange of new CSF with extracellular fluid, and (3) efferent flow of the mixed CSF/ISF along the para-venous space. The entire process is facilitated by AQP4 water channels expressed on the astrocytic endfeet. The figure was created using online BioRender software (BioRender.com). AQP4, aquaporin-4; CSF, cerebrospinal fluid; ISF, interstitial fluid.

Figure 2.

Physiological functions of the glymphatic system. By regulating extracellular fluid influx and efflux, the glymphatic system is involved in transporting immune cells and balancing brain immunity, assisting local volume transmission, transporting nutrients, and clearing extracellular metabolites and waste products from the brain parenchyma. The figure was created using online BioRender software (BioRender.com). CSF, cerebrospinal fluid; CVO, circumventricular organs; DC, dendritic cells; ISF, interstitial fluid; PVS, perivascular space.

Figure 3.

Routes of CSF efflux in humans. Outflow routes of cranial CSF (blue-green arrows) involve perineural sheaths surrounding cranial and spinal nerves, mLVs, and arachnoid villi/granulations. Experimental evidence in rodents and humans strongly supports CSF outflow along the olfactory nerve through the cribriform plate and towards nasal mucosa lymphatic vessels. Finally, the CSF drains into the dCLNs. The figure was created using online BioRender software (BioRender.com). CSF, cerebrospinal fluid; dCLNs, deep cervical lymph nodes; mLVs, meningeal lymphatic vessels.

Figure 4.

(a) In addition to the blood, the brain transport system may be a crucial component in CNS immune surveillance because it drains antigens as well as antigen-presenting and other immune cells from the brain parenchyma into CLNs for sampling and processing. (b) Convective flow of amyloid-β via the brain glymphatic-mLV system may facilitate the protein’s BBB transport. (c) Overall scheme of the brain drainage system, and especially the brain lymphatic drainage system. (1) CSF is mainly produced by the choroid plexus. (2) Arterial wall pulsations drive CSF deep into the brain along perivascular spaces. (3) CSF enters the brain parenchyma supported by AQP4 water channels and disperses within the neuropil. (4) ISF mixes with CSF and accumulates in the perivenous space, then drains out of the brain via (5) mLVs and veins, as well as along cranial and spinal nerves. Segments (2)–(4) are described in detail in Figure 1, while segment (5) is described in detail in Figure 3. The figure was created using online BioRender software (BioRender.com). Aβ, amyloid-β; AQP4, aquaporin-4; BBB, blood-brain barrier; BCSFB, blood–cerebrospinal fluid barrier; CLNs, cervical lymph nodes; CNS, central nervous system; CSF, cerebrospinal fluid; ISF, interstitial fluid; LV, lateral ventricle; mLVs, meningeal lymphatic vessels; PVS, perivascular space.

Figure 5.

Pathological changes in the glymphatic-mLV system and related neurological diseases. A reduction in glymphatic fluid transport has been documented during healthy aging and in some neurological disorders, such as acute ischemic stroke (AIS), subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), Alzheimer's disease, and idiopathic normal pressure hydrocephalus (iNPH). In addition, mLVs have been implicated in glioblastoma (GBM) and multiple sclerosis (MS). The mLVs act as conduits connecting the central nervous system and peripheral immunity: they transport numerous immune cells and antigens to dCLNs or to the CNS. The figure was created with online BioRender software (BioRender.com). Aβ, amyloid-β; CSF, cerebrospinal fluid; EAE, experimental autoimmune encephalitis; DC, dendritic cells; dCLNs, deep cervical lymph nodes; GFAP, glial fibrillary acidic protein; mLVs, meningeal lymphatic vessels; NSE, neuron-specific enolase; PVS, perivascular space.