Understanding the Glymphatic System
Material below is adapted from the SfN Short Course The Glymphatic System, by Nadia Aalling, MSc, Anne Sofie Finmann Munk, BSc, Iben Lundgaard, PhD, and Maiken Nedergaard, MD, DMSc. Short Courses are daylong scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
The glymphatic system is a network of vessels that clear waste from the central nervous system (CNS), mostly during sleep. Recent evidence suggests that the glymphatic system may be disrupted in and contribute to some diseases of the brain.
Cerebrospinal fluid (CSF) flows alongside the arteries and is forced into the spaces next to the smaller blood vessels that enter the brain. There, it interchanges with interstitial fluid — the fluid surrounding the brain’s cells — often through a channel expressed by astrocytes, glial cells whose feet surround the space around the brain’s capillaries, forming the glymphatic vasculature.
Glymphatic transport uses energy from arteries pulsing and from the pressure created as CSF is made, as well as from as yet unknown forces. This interchange results in the collection of waste products, such as metabolites and proteins, and their transfer to CSF, which carries them out of the brain to sites where CSF drains.
The glymphatic system is most active during sleep in rodents, and least active while the animals are awake.
Researchers have shown that while animals are sleeping, the interstitial space also increases in volume, suggesting that increased glymphatic activity is made possible by the greater availability of space for the interchange between interstitial and cerebrospinal fluid.
Sleep deprivation affects the system by influencing the location of the astrocyte-expressed channel through which much of the interchange takes place. Aging also disrupts glymphatic function and the correct localization of this channel, but exercise can mitigate aging’s detrimental effects in mice, which points to one possible way in which exercise is neuroprotective.
Reasons that aging could disrupt glymphatic function include: decreased CSF, decreased flexibility and therefore pulsing of the arteries, and changes in the glial cells that create the glymphatic vessels. Brain aging is one of the primary contributing factors to developing neurological disease.
A primary cause of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is protein aggregation.
During sleep or anesthesia in rodents, the glymphatic system clears aggregated proteins such as amyloid beta, the main component of the plaques that form in the brain during AD. Build up of amyloid beta protein could further reduce glymphatic transport. People with AD sleep less well than their healthy counterparts, which could also reduce glymphatic system function.
In addition to its possible function in AD, glymphatic system impairment may also play a role in traumatic brain injury, cortical spreading depression, and stroke.
Animal models have shown that reduced glymphatic transport may precede the development of AD; therefore, scientists hypothesize that increasing glymphatic transport could postpone the onset of the disease.
The finding that exercise appears to maintain glymphatic function could lead to new treatments that will likely be most effective when used early in disease onset. Ways to assess glymphatic flow with magnetic resonance imaging or positive emission tomography are currently under development as clinical diagnostic tools.
It is also possible that future work on the glymphatic system will reveal functions for it beyond waste clearance, such as delivery of growth factors or drugs.