Meningeal Lymphatic Vessels: A Drain of the Brain Involved in Neurodegeneration?

Neurodegenerative diseases include several kinds of neurological disorder that are caused by the progressive death of neurons in different regions of the brain. Such diseases affect millions of people worldwide and impose a heavy health burden on modern societies. However, their pathogenesis remains elusive, and disease-modifying methods are not currently available to prevent, halt, or reverse them [1]. A common feature of neurodegenerative diseases is that the abnormal accumulation of misfolded proteins, such as amyloid beta (Aβ), tau, α-synuclein, fused in sarcoma (FUS), and TAR DNA-binding protein 43 (TDP-43) in the brain leads to selective neuronal degeneration and dysfunction. Dysfunction in the removal of these misfolded proteins from the brain is thought to be a major cause of neurodegenerative diseases and a major therapeutic target for their cure.

Nearly all the tissues and organs, except for the central nervous system (CNS), have been found to include a lymphatic vasculature, which removes the metabolic waste from the tissue to the blood circulation. The CNS was traditionally thought to be devoid of parenchymal lymphatic vessels. For years, there had been speculation about the existence of lymphatic vessels in the brain, but clear evidence was lacking and this remained a puzzle.

A recent breakthrough in this field was the discovery of the glymphatic system [2], which was identified as a clearance pathway in the rodent brain. This route moves cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and successively into the interstitium, then guides flow towards the venous perivascular spaces, eventually removing metabolic waste in the parenchyma to the CSF. This system was named the “glymphatic” system due to the glial-like water flux and its lymphatic system-like function. It is not a true lymphoid tissue, so sometimes it is referred to as “lymphoid-like” tissue. Another milestone was achieved in 2015 when two studies in mice provided direct evidence that the brain does, in fact, have a lymphatic system [3, 4]. These lymphatic vessels extend through the dura mater and run along the peri-sinus space of the superior sagittal and transverse sinuses. Nevertheless, the major exit route for CSF was unknown. Recently, researchers have shown that lymphatic vessels at the base of the rodent skull are specialized to drain CSF and allow waste and other macromolecules to leave the brain. This provides a deeper understanding of the anatomy and functions of the lymphatic system in the brain, and represents a novel therapeutic approach for neurodegenerative diseases, according to a new research recently published in Nature [5].

Due to the complicated bony architecture at the base of the skull, research in this area remains technically difficult. A study in mice has shown that, from very early days after birth, meningeal lymphatic vessels (mLVs) grow from the base of the skull along the blood vessels into a complex network that extends to the dorsal part of the skull. Based on this finding, Ahn et al. [5] explored the function of brain lymphatic vessels using Prox1–GFP lymphatic reporter mice, which express green fluorescent protein under the promoter of Prox1, a key gene in lymphatic development, and enable researchers to expediently visualize the detailed structure and morphology of lymphatic vessels. The authors demonstrated that dorsal mLVs show mostly a continuously-sealed zipper-like junctional pattern of lymphatic endothelial cells, while the basal mLVs consist principally of a discontinuously-sealed button-like junctional pattern similar to that of lymphatic capillaries in peripheral organs, suggesting that they are suitable for taking up CSF macromolecules. Furthermore, studies have shown that large molecular tracers, when infused into the lateral ventricle, rapidly reach lymph nodes via perineural routes through foramina in the skull. However, Ahn and colleagues reported that the basal mLVs drain directly into the deep cervical lymph nodes. Next, the authors assessed the drainage function of mLVs. When they followed the CSF drainage using contrast agents with magnetic resonance in rats, and a fluorescently-labeled tracer in mice, they found that tracers injected into the interstitial fluid of brain tissue were absorbed by the basal meningeal vessels and then drained out of the brain. Moreover, the researchers did not see any uptake by dorsal vessels. Overall, based on these anatomical and functional experiments, the authors came to the conclusion that basal rather than dorsal mLVs are the main route for macromolecule uptake and drainage of CSF into the peripheral lymphatic system [5].

What is the pathophysiological significance of the brain lymphatic system? It has been suggested that aged mice have reduced turnover and drainage of CSF, and such a decline in drainage might have implications for neurodegenerative diseases. Although lymphatic vessels show extraordinary plasticity, the changes in mLVs associated with aging remain unclear. Ahn and colleagues, therefore, compared the changes in basal and dorsal mLVs with age using young and aged mice, and found that the aged mice show clear regression of dorsal mLVs compared with young mice. By contrast, the basal mLVs in aged mice are enlarged and more branched and hyperplastic compared with young mice. This misshapen pattern may compensate for poor drainage. A previous study reported that disrupted lymphatic endothelial cell junctions always occur when lymphatic drainage is impaired and this has been proposed to be one of the initial factors for age-related lymphatic vessel dysfunction and degeneration. So, what happens to these structures with age? The authors showed that the transport of tracer through the basal mLVs in aged mice is significantly lower than in young mice, although lymphatic endothelial cells in aged basal mLVs have fewer zipper-type junctions and more button-type junctions, suggesting that these age-related changes in basal mLVs are associated with decreased CSF drainage in aged mice. Nevertheless, the breakthrough in the precise routes for CSF drainage is a critical step towards understanding how metabolic waste is cleared from the CNS.

Accumulation of toxic protein aggregates is the common pathological hallmark of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, Huntington’s disease, and motor neuron diseases. In AD, an imbalance between Aβ production and clearance is regarded as the cause of Aβ accumulation. Findings in recent years suggest that extracellular Aβ deposits are removed from the brain by various means, including enzymatic degradation, phagocytosis by microglia, glymphatic clearance from parenchyma to CSF, a blood–brain barrier (BBB) route, and the recently-identified lymphatic pathway (Fig. 1). The BBB and brain lymphatic pathways are approaches for transporting metabolic waste from the brain to the periphery, but the extent of their contribution to removing waste remains largely unclear. Recent studies suggest that ~40% of the Aβ peptide generated in the brain is cleared by transport to the periphery [6], as is ~19% of the pathological tau protein in the brain [7]. These findings imply that there are physiological mechanisms to transport both intracellular and extracellular pathological proteins from the brain to the periphery for clearance. Therefore, the transportation between brain and periphery would play a critical role in the clearance of metabolic waste and the maintenance of homeostasis in the brain. In this regard, dysfunction of the draining system would be an important factor leading to the development of neurodegenerative diseases. It is important to note that the function of the brain lymphatic system draining the CSF from the brain to the periphery declines during aging as shown in Ahn’s study and a previous study, leading to the accumulation of Aβ in the brain of AD mice [5, 8]. These findings shed light on the pathophysiological action of the brain lymphatic system.

Fig. 1.

Pathways of cerebrospinal fluid (CSF) drainage from the brain to the periphery. ① Meningeal lymphatics pathway: CSF flows to meningeal lymphatic vessels mainly via the basal component, and then flows to the deep cervical lymph nodes. ② Venous sinus pathway: CSF drains directly into the venous sinuses via arachnoid villi. ③ Perineural pathway: CSF drains to the cervical lymph nodes along cranial nerves (such as the olfactory, optic, and trigeminal nerves). ④ Glymphatic and paravascular pathways: CSF flows from the subarachnoid space into the brain parenchyma via peri-arterial spaces, exchanges with interstitial fluid (ISF), then flows back to the subarachnoid space via peri-venous spaces. ⑤ Perivascular pathway: ISF diffuses through extracellular spaces in the brain, enters through basement membranes in the tunica media of arteries, and eventually drains from the brain parenchyma to the cervical lymph nodes along perivascular pathways. ⑥ Blood-brain barrier (BBB) pathway: ISF drains from the brain parenchyma into the blood via the BBB. Impairment of these pathways is thought to result in the abnormal accumulation of metabolic waste and pathological proteins, such as Aβ and phosphorylated tau, in the brain.

A critical question is how important the lymphatic system is in clearing metabolic waste from the brain. There are several pathways for substance exchange between the brain and the periphery, including the BBB, choroid plexus, subarachnoid granulations, and the lymphatic system. However, it is essential to determine how the lymphatic system cooperates with other clearance mechanisms in the brain to clear metabolites. We need to know how much CSF is drained into the peripheral circulation via the lymphatic system. If this amount is limited, the brain lymphatic system may mainly function in immune regulation rather than waste clearance. The answer to this basic question will pave the way to understanding the roles of the brain lymphatic system in the pathogenesis of neurodegenerative diseases as well as the development of therapeutics and interventions.

Although the relative contribution of each of these systems to overall clearance is unknown, they work together to drain pathological proteins from the brain to the periphery, suggesting that the peripheral tissues and organs are physiologically important in maintaining homeostasis in the brain [9]. However, how the pathological proteins of neurodegeneration such as Aβ are cleared from the periphery after drainage from the brain is poorly understood. In fact, several peripheral organs and cells, such as liver, kidney, and monocytes, are thought to participate in Aβ catabolism and constitute potential Aβ clearance pathways. However, direct evidence for their roles in Aβ clearance is lacking. A decline in peripheral Aβ clearance might also impede the efflux of Aβ from the brain to the periphery, and thereby attenuate the central clearance of Aβ. In contrast, strengthening the peripheral clearance of waste alleviates Aβ and tau-related pathologies in the brain [6, 7], and might, therefore, represent a new therapeutic approach for neurodegenerative diseases.

Neurodegenerative diseases such as AD are traditionally regarded as disorders of the brain itself. However, growing evidence suggests that Aβ metabolism in the brain is dynamically correlated with Aβ metabolism in the periphery [10], and pathological α-synuclein in the brain has been shown to be derived from the intestine, suggesting that the neurodegenerative diseases might be systemic disorders [9]. The discovery of the brain lymphatic system reveals a novel connection between brain and periphery, and opens a new approach to a systematic and comprehensive understanding of the pathogeneses and to the development of interventions for neurodegenerative diseases.

Conflict of interest

The authors declare no financial or other conflicts of interests.