Reviewing the Role of the Glymphatic System in Brain Aging

That the brain has a lymphatic system is a comparatively recent realization. It coincides with another recent realization that perhaps drainage of fluid from the brain is important in maintaining brain health, carrying away molecular waste that would otherwise accumulate to cause pathology. Common age-related neurodegenerative diseases are characterized by rising inflammation and increasing presence of protein aggregates and other molecular waste in the brain, and it is now known that drainage pathways from the brain to the body are impaired with age. It remains to be seen how well restored drainage performs as a basis for therapy, though Leucadia Therapeutics nears human clinical trials of their implant to restore cerebrospinal fluid drainage through the cribriform plate, a different pathway from the glymphatic system that is more relevant to the onset of Alzheimer's disease.

It was traditionally believed that the lymphatic system didn't exist in the central nervous system. Thus, cell debris, potential neurotoxic proteins, and other metabolites with large molecular weight were considered to be removed in a different clearance pathway than brain vasculature. In 2012, the researchers found that cerebrospinal fluid (CSF) can enter brain parenchyma and exchange with brain interstitial fluid (ISF) in the presence of aquaporin-4 (AQP4) on astrocytes. Likewise, when the mixed fluid was drained from the brain, Amyloid-β (Aβ) was transported along with the outflow. Since the function of this "drainage" pathway is similar to that of the lymphatic system and supported by astrocytes, it was named the glymphatic system after the role of glia cells.

Since last decade, many researchers in the field of neurology, neurodegenerative diseases and physiology have aimed to study and develop the glymphatic system, providing a brand-new perspective for us to understand brain diseases: the overall fluid flow of the brain rather than a specific lesion or structure. Herein, we summarized the components of the glymphatic system, the fluid circulation mode within this system, how pathogenic solutes are transported in certain diseases, affecting factors of its function, and by what means we can study the glymphatic system. It may provide direction and reference for brain diseases and medical researchers.


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