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Review
. 2023 Jun 15:15:1179988.
doi: 10.3389/fnagi.2023.1179988. eCollection 2023.

The glymphatic system: a new perspective on brain diseases

Zhao Ding  1 , Xiaodi Fan  1 , Yehao Zhang  1 , Mingjiang Yao  1 , Guangrui Wang  1 , Yilei Dong  1 , Jianxun Liu  1 , Wenting Song  1
Affiliations
Review

The glymphatic system: a new perspective on brain diseases

Zhao Ding et al. Front Aging Neurosci. .

Abstract

The glymphatic system is a brain-wide perivascular pathway driven by aquaporin-4 on the endfeet of astrocytes, which can deliver nutrients and active substances to the brain parenchyma through periarterial cerebrospinal fluid (CSF) influx pathway and remove metabolic wastes through perivenous clearance routes. This paper summarizes the composition, overall fluid flow, solute transport, related diseases, affecting factors, and preclinical research methods of the glymphatic system. In doing so, we aim to provide direction and reference for more relevant researchers in the future.

Keywords: AQP-4; astrocytes; cerebrospinal fluid; perivascular spaces; the glymphatic system.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The structure of VRS. VRS is an annular tunnel space around penetrating arterioles in the brain parenchyma, filled with CSF. CSF can enter the brain parenchyma through PVS.
FIGURE 2
FIGURE 2
The distribution of AQP-4. AQP4 is located at the ependymal cells and the astrocyte processes (which face CSF–brain and blood–brain barriers).
FIGURE 3
FIGURE 3
Functional diagram of the glymphatic system. CSF delivers nutrients and neuroactive substances to the brain parenchyma through the peri-arterial spaces pathway and mixes with ISF in the brain parenchyma. The mix of CSF and ISF removes metabolic wastes through peri-venous clearance routes.
FIGURE 4
FIGURE 4
The composition of BBB and B-CSFB. The composition of BBB: A layer of endothelial cells interconnected through tight junctions and not containing fenestrations, basal membrane consisting of the basal lamina of astrocytes and basal lamina of endothelial cells, protrusions of astrocytes (Zhang et al., 2022). The composition of B-CSFB: choroidal epithelial cells interconnected by tight junctions (which are more permeable than the junctions between the endothelial cells of brain capillaries), basal membrane, endothelium of the pia mater capillaries containing fenestrations (Jessen et al., 2015).
FIGURE 5
FIGURE 5
(A) The fluid circulation in the glymphatic system (Rasmussen et al., 2018). Blood generates CSF through choroid plexus capillary endothelial cells distributed in the lateral, third, and fourth ventricle. CSF flows from the ventricular system to the subarachnoid space of the brain and spinal cord. CSF in the subarachnoid space enters brain parenchyma through the perivascular spaces of penetrating arteries, which AQP4 drives on the end feet of astrocytes. Additionally, CSF mixes with ISF in brain parenchyma. The mixture of CSF and ISF subsequently enters the perivenous space. Egress sites of cranial fluid (orange arrows) fall into three functional categories: the perineural sheaths surrounding cranial and spinal nerves, dural lymphatic vessels, and arachnoid granulations. Finally, the mixture of CSF and ISF is drained to the cervical lymph nodes. (B) The fluid circulation in the glymphatic system.
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