| Neuroscience/ Translational neurology  

The glymphatic system: an update

The glymphatic system is a brain‑wide system thought to help clear waste products from the central nervous system. It appears to work in close interaction with sleep, particularly deep NREM sleep, and may be one way in which sleep supports long‑term brain function. This Neurology Update presents a brief overview of the glymphatic system, starting with its discovery and outlining how the concept has expanded, including proposed links to neurological disease.

The glymphatic system, discovered by Maiken Nedergaard in 2012 (1), has significantly advanced our understanding of how the brain eliminates waste. This system derives its name from the lymphatic system in the body, as it facilitates the removal of waste and fluids with the assistance of glial cells, hence the term "glymphatic." Dysfunctions within the glymphatic system are believed to be linked to various neurological disorders, including Alzheimer’s disease, Parkinson’s disease and epilepsy.

Perivascular channels, formed by the endfeet of astrocytes and the walls of blood vessels, play a crucial role in this system. During sleep, particularly during non‑rapid eye movement (NREM) sleep, the walls of blood vessels pulsate while the astrocytic endfeet remain relatively stationary. This creates a pump‑like effect that propels cerebrospinal fluid into the interstitial space, where it mixes with interstitial fluid and is ultimately cleared through perivenous routes. Astrocytes express a water channel known as AQP4 on their endfeet, and these channels are believed to be critical for effective fluid movement and waste clearance. In 2015, Louveau et al. discovered lymphatic vessels in the dura mater and showed that these vessels drain fluid to the deep cervical lymph nodes (2). This finding helped identify a previously missing link between glymphatic clearance within the brain parenchyma and drainage to the peripheral lymphatic system.

The glymphatic system was initially identified in rodent models, but in 2018, the first publication involving human subjects appeared. In this study, Ringstad et al. utilized MRI and intrathecal contrast injection to visualize glymphatic flux in humans, demonstrating that sleep deprivation markedly slows the clearance of tracers from the brain (3). Among the waste products that the glymphatic system is thought to eliminate are neurotoxic proteins, such as amyloid-beta and tau (4). A study by Harrison et al., from 2020 (5), found that impaired glymphatic clearance significantly accelerated tau protein accumulation in mouse models of Alzheimer’s disease. These findings further establish the glymphatic system as a critical factor in neurodegeneration and suggested the possibility of AQP4 as a potential therapeutic target for Alzheimer’s disease and other tauopathies. This discovery has also intensified the focus on sleep as an essential component of brain health, potentially reducing the risk of disorders such as dementia.

It is important to note that there is  an ongoing debate regarding the glymphatic system and its underlying mechanisms and relevance in humans. Key discussions focus on whether waste clearance is driven by bulk fluid flow or diffusion, the applicability of animal data to human physiology, and concerns about potential methodological artifacts arising from imaging and tracer studies (6,7). Further experiments are necessary to achieve a better understanding of the glymphatic system and its implications for health and disease.

Key Points:

  • The glymphatic system was first described in animal studies by Maiken Nedergaard and colleagues and later expanded by several groups.
  • It refers to a brain‑wide, lymphatic‑like clearance pathway that helps remove metabolic waste and solutes from the central nervous system.
  • Although many aspects remain uncertain, glymphatic function appears closely linked to sleep and may contribute to the pathophysiology of several neurological disorders, with dementia being the most extensively studied.

References:

  1. Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., ... & Nedergaard, M. (2012). A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science translational medicine, 4(147), 147ra111-147ra111.
  2. Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., ... & Kipnis, J. (2015). Structural and functional features of central nervous system lymphatic vessels. Nature, 523(7560), 337-341.
  3. Ringstad, G., Valnes, L. M., Dale, A. M., Pripp, A. H., Vatnehol, S. A. S., Emblem, K. E., ... & Eide, P. K. (2018). Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI insight, 3(13), e121537.
  4. Iliff, J. J., Chen, M. J., Plog, B. A., Zeppenfeld, D. M., Soltero, M., Yang, L., ... & Nedergaard, M. (2014). Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. Journal of Neuroscience, 34(49), 16180-16193.
  5. Harrison, I. F., Ismail, O., Machhada, A., Colgan, N., Ohene, Y., Nahavandi, P., ... & Lythgoe, M. F. (2020). Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model. Brain, 143(8), 2576-2593.
  6. Smith, A. J., Yao, X., Dix, J. A., Jin, B. J., & Verkman, A. S. (2017). Test of the'glymphatic'hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. elife, 6, e27679.
  7. Miao, A., Luo, T., Hsieh, B., Edge, C. J., Gridley, M., Wong, R. T. C., ... & Franks, N. P. (2024). Brain clearance is reduced during sleep and anesthesia. Nature neuroscience, 27(6), 1046-1050.

Publish on behalf of the Coordinating Panel on Neuroscience/ Translational Neurology

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