Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS

Abstract

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term "glymphatic" (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer's disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood-brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.

Keywords: blood–brain barrier; glymphatic system; lymphatic system; neurodegenerative diseases; neurovascular unit.

FIGURE 1

Glymphatic system, neurovascular unit (NVU), and the blood–brain-barrier. The glymphatic system contributes to the transport of nutrients and signaling molecules into the brain parenchyma meanwhile promoting the clearance of proteins and interstitial waste solutes out of the brain. Subarachnoid CSF enters the brain parenchyma via para-arterial spaces and then mixes with the interstitial fluid (ISF) and waste solutes in the parenchyma. Whether this occurs through convective bulk flow or diffusion remains debated. The resulting CSF-ISF fluid exchange and the interstitial waste solutes enter the paravenous space through gaps between the astrocytic end-feet to be drained either back to the CSF-dural sinus-meningeal lymphatic vessels, or to the deep cervical lymph nodes. Green arrows and shades indicate the CSF and CSF-ISF fluid transport, while black stars indicate the interstitial waste solutes that exit the parenchyma via the paravenous efflux pathway. The insert depicts the main components of the NVU at the level of intraparenchymal capillaries, including perivascular astrocytes with their end-feet, neurons, microglia, pericytes, endothelial cells (ECs), and basement membrane (basal lamina). Capillary ECs are held together by tight junctions forming the blood–brain barrier (BBB), where the different transport routes are represented, including transcellular lipophilic transport, carrier protein-mediated transport, paracellular aqueous transport, receptor-mediated transcytosis, as well as adsorptive and cell-mediated transcytosis.

FIGURE 2

Glymphatic pathway in pathological conditions: a role for the bidirectional gut-brain communication. Alterations of the glymphatic pathway may contribute to the extracellular accumulation of waste products, including altered protein in the brain (black stars). These include alterations in the morphology and drainage capacity of meningeal lymphatic vessels, impairment of CSF influx and efflux, along with the release of several pro-inflammatory cytokines and immune cells. Considering the reciprocal communication which occurs between the brain and the gastrointestinal tract, gut alterations can affect the CNS, and vice-versa. Potentially harmful solutes, including misfolded/aggregated proteins, may spread to the gut through the autonomic nervous system to induce inflammation [brain-first (top-down) type]. In turn, gut dysbiosis, inflammation, and leakage may promote the antidromic spread of potentially harmful molecules to the CNS via the vagal fibers or the bloodstream [body-first (bottom-up) type], bypassing and altering the glymphatic system and the BBB (left insert). These include misfolded/aggregated proteins such as α-synuclein, microorganisms, and also pro-inflammatory cytokines and activated immune cells, such as TREM TREM cells-positive activated macrophages. Extracellular accumulation of waste products related to an altered glymphatic drainage is exacerbated when intracellular clearing systems are impaired (right insert). This is the case of the autophagy pathway, which grants neuronal proteostasis and survival. When autophagy is impaired, extracellular release of undigested, potentially harmful substrates may occur via exosome release.