The Glymphatic System in Stroke

The glymphatic system is a comparatively recently discovered feature of the brain, a drainage path for cerebrospinal fluid (CSF) that appears to become dysfunctional with age. That dysfunction may contribute to the progression of neurodegenerative conditions by allowing molecular waste, such as misfolded proteins, to build up in the brain. This is distinct from the age-related dysfunction of CSF drainage through the cribriform plate that may be a root cause of Alzheimer's disease, as that drainage is localized to the part of the brain in which Alzheimer's originates. Given that the glymphatic system is only recently characterized, many researchers interested in age-related conditions affecting the brain are still engaged in incorporating it into their view of risk, pathology, and potential treatments. Here, stroke and its aftermath, and potential connections to the glymphatic system, is the topic of interest.

Clearing the metabolic wastes and maintaining the fluid homeostasis are important for brain function. In most organs, the lymphatic network is responsible for the wastes clearance and fluid drainage. However, a hallmark of the brain is the absence of typical lymphatic structures. Due to the presence of blood-brain barrier (BBB), the movement of solutes and ions in the brain is strictly restricted. Cerebrospinal fluid (CSF) has been considered to be important for the exchange of water-soluble metabolites; however, its mechanisms remain largely unknown. In 2012 researchers reported the existence of the glymphatic system (GS) in the central nervous system (CNS), which is an alternative clearance system located in the perivascular space and aquaporin-4 (AQP4) dependent. Emerging evidence from human studies and rodent models suggests that the GS is crucial for maintaining brain health, and dysfunction of GS is closely associated with various neurological disorders, including aging, neurodegeneration, and acute brain injury. In parallel, the meningeal lymphatic vessels were discovered and demonstrated to participate in solutes transport and in immune surveillance.

Stroke, a major cause of death and disability, affects over 800,000 individuals annually. It has been well-recognized that the GS plays a crucial role in the pathophysiology of stroke, including brain edema, blood-brain barrier (BBB) disruption, immune cell infiltration, neuroinflammation, and neuronal apoptosis. Targeting the GS, therefore, has provided potential for the early risk assessment, diagnosis, prognosis, and therapeutic of stroke. In this review, we summarize the latest research progress in the GS, including the anatomy and function, the interaction with the meningeal lymphatic systems and the BBB, and the communication between astrocytes and other GS cellular components. We emphasize the role of the GS in pathophysiology of different stroke subtypes, especially the role of AQP4 in the pathophysiology of stroke.

Link: https://doi.org/10.3389/fnagi.2021.689098

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