The Glymphatic System . . . "an undiscovered system for clearing proteins and other wastes from the brain." [o]
How to optimise your brain's waste disposal system
The human brain can be compared to something like a big, bustling city. It has workers, the neurons and glial cells which co-operate with each other to process information; it has offices, the clusters of cells that work together to achieve specific tasks; it has highways, the fibre bundles that transfer information across long distances; and it has centralised hubs, the densely interconnected nodes that integrate information from its distributed networks.
Like any big city, the brain also produces large amounts of waste products, which have to be cleared away so that they do not clog up its delicate moving parts. Until very recently, though, we knew very little about how this happens. The brain’s waste disposal system has now been identified. We now know that it operates while we sleep at night, just like the waste collectors in most big cities, and the latest research suggests that certain sleeping positions might make it more efficient.
Waste from the rest of the body is cleared away by the lymphatic system, which makes and transports a fluid called lymph. The lymphatic system is an important component of the immune system. Lymph contains white blood cells that can kill microbes and mop up their remains and other cellular debris. It is carried in branching vessels to every organ and body part, and passes through them, via the spaces between their cells, picking up waste materials. It is then drained, filtered, and recirculated.
[It] worked best in mice lying on their sides compared to those lying on their back or standing up.
The brain was thought to lack lymphatic vessels altogether, and so its waste disposal system proved to be far more elusive. Several years ago, however, Maiken Nedergaard of the University of Rochester Medical Center and colleagues identified a system of hydraulic “pipes” running alongside blood vessels in the mouse brain. Using in vivo two-photon imaging to trace the movements of fluorescent markers, they showed that these vessels carry cerebrospinal fluid around the brain, and that the fluid enters inter-cellular spaces in the brain tissue, picking up waste on its way.
Nedergaard and her colleagues also discovered that proper function of these vessels depends on movements of water around the brain, which are carried out by glial cells called astrocytes, and therefore named them the glymphatic system. They went on to show that inter-cellular spaces expand by up to 60% in the brains of naturally sleeping and anaesthetised mice, and that this expansion drives the clearance of waste from the brain by facilitating the movements of lymph and water.
In the fall of 2015, researchers from the University of Virginia reported the identification of lymphatic vessels in the central nervous system. They demonstrated that the lymphatic system extends into the dura mater, the thickest and outer-most of the three meningeal membranes that envelope the brain and spinal cord. These vessels run parallel to the major veins and arteries, and split to send branches deep into the brain’s crevices. The researchers believe that they could be linked to the glymphatic system, and may be the second stage of the disposal mechanism, which would transport waste out of the brain and spinal cord altogether.
The lymph system. [o]
The latest study from Nedergaard’s group, published in the Journal of Neuroscience earlier this month, shows that body posture affects the efficiency of the glymphatic system’s waste clearance. Using fluorescence microscopy and radioactive tracing once again, they showed that drainage of the cerebrospinal fluid worked best in mice lying on their sides compared to those lying on their back or standing up.
The function of sleep was once deeply mysterious, but there’s plenty of evidence that it is critical for memory consolidation, and it would now seem to be required for the effective removal of waste from the brain, too. Although these studies were performed in mice, preliminary results suggest that lymphatic vessels are also present in the human brain and spinal cord, but further research will be needed to confirm that they actually constitute a working waste disposal system.
Eventually, the link to sleep could have important implications for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s, all of which involve the build-up of misfolded proteins within and around nerve cells, because of a defective waste disposal system. Indeed, it is now seems clear that good sleep hygiene has a neuroprotective effect and, in line with this, other research shows that sleep disturbances predict the onset of neurodegeneration.
Sleeping on the side just happens to be the most popular sleeping posture for both mice and humans, and so this preference may have evolved to optimise the waste disposal system and thus ensure that the metropolis of the brain runs as effectively as possible.
Lee, H. et al. (2015). 'The Effect of Body Posture on Brain Glymphatic Transport.' J. Neurosci, 35: 11034-44. DOI: 10.1523/JNEUROSCI.1625-15.2015.
Louveau, A., et al. (2015). 'Structural and functional features of central nervous system lymphatic vessels.' Nature, 523: 337-41. DOI: 10.1038/nature14432.
Xu, L., et al. (2014). 'Sleep Drives Metabolite Clearance from the Adult Brain.' Science, 342: 373-7. DOI: 10.1126/science.1241224. [Full text]
Iliff, J., et al. (2013). 'A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes,' Including Amyloid β. Sci. Trans. Med., 4: 147ra111. DOI: 10.1126/scitranslmed.3003748. [Full text]
This article, written for a more general audience, first appeared in The Guardian, August 22, 2015.
Cleaning the Dirty Brain?
Every organ in the body contains a system of nodes and vessels that helps rid the body of toxins and waste products. The lymphatic system transports a clear fluid called lymph, which constantly flows through the vessels — fighting infection and picking up waste products — before being filtered through the nodes and then draining back into the bloodstream.
Until very recently, it was thought that the lymphatic system did not extend into the brain, and that the brain recycles, rather than disposes of, its waste products. About five years ago, however, came the discovery of the glymphatic system — the brain's waste disposal system. We now know that the glymphatic system is also involved in neurodegenerative conditions such as Alzheimer's and Huntington's diseases. Researchers discussed its potential roles in the course of these diseases at a one-day symposium called Clearing the Brain: Protein Clearance in Neurodegenerative Disease, held recently at University College London.
“You can say neurodegenerative diseases are diseases of a dirty brain,” says Maiken Nedergaard, who was among the researchers who first described the brain's waste disposal system properly in 2012. “But how does the healthy functioning brain get rid of these proteins?”
[Brain pulsations] drive fluid into the brain and, like a filter in an aquarium, filter away everything outside the cells . . .
To investigate, Nedergaard, now at the University of Copenhagen, and her colleagues began injecting fluorescent “marker” molecules into the brains of live mice, and used an imaging technique called two-photon microscopy to watch the movements of the markers in real time. This revealed a network of vessels that run parallel to the blood vessels on the surface of the brain. It's now thought that cerebrospinal fluid (CSF), which acts as a sink for the brain's waste products, drains into these vessels.
Nedergaard's group and others have also shown that the flow of CSF through the glymphatic system depends on aquaporin-4, a water channel protein found at high density in the “endfeet” of non-neuronal cells called astrocytes, which come into contact with both blood vessels and the spaces containing cerebrospinal fluid. Research also shows that the glymphatic system works mainly during sleep, and that it seems to work best when we sleep in a certain position.
“[Brain pulsations] drive fluid into the brain and, like a filter in an aquarium, filter away everything outside the cells,” Nedergaard explained. “It makes sense to have water channels in the astrocyte endfeet, because this is where CSF enters the brain to clean the waste.”
WHAT CAN GO AWRY
Jeffrey Iliff of Oregon Health and Science University in Portland, who worked with Nedergaard on characterising the glymphatic system, described for the audience the evidence for dysfunction of the glymphatic system in Alzheimer's disease.
Like some other neurodegenerative diseases, Alzheimer's is characterised by misfolded proteins that aggregate within cells and in the spaces between them. In some, but not all, of these diseases, the insoluble protein clumps are toxic to the cells, and so targeting the aggregation process, or the process by which the clumps are cleared from the brain, could be of potential therapeutic benefit.
In an early study, Iliff and Nedergaard showed that flourescently-labelled amyloid-beta, one of the proteins linked to Alzheimer's, is transported through the glymphatic system of mice, and that deleting the Aquaporin-4 gene prevented the clearance of amyloid-beta from the animals' brains. They have also shown that functioning of the glymphatic system decreases with age in mice, leading to a significant reduction in the efficiency of CSF drainage, and that this is associated with widespread loss of aquaporin-4 water channels from astrocyte endfeet and reduced pulsatility of blood vessel walls.
The brain’s glymphatic system is a waste clearance system that surrounds the arteries and veins of the brain. It is composed of a system of astroglial cells and their aquaporin channels. The picture above gives a better idea. [o]
Others have shown, in mouse models of Alzheimer's, that amyloid-beta levels in the lymph nodes increase with age, and that functioning of the glymphatic system is impaired prior to amyloid-beta aggregation in the brain, one of the pathological hallmarks of the disease.
Earlier this year, Iliff's team published a post-mortem study showing that aquaporin-4 distribution is also altered in the brains of people diagnosed with Alzheimer's. More recently, they published evidence that certain variants of the aquaporin-4 gene influence the rate of cognitive decline in people with Alzheimer's: Two variants were associated with a faster rate of decline, and two others associated with a slower rate.
“This corroborates the data coming from animal studies, which suggests that altered functioning of the aquaporin-4 gene underlies some of the vulnerability to Alzheimer's Disease,” said Illif, adding that the observation that the glymphatic system functions mainly at night fits nicely with other research linking neurodegeneration with sleep disturbances. “I think we're in an exciting place where work in humans over the past year is beginning to clarify the biology and clinical significance [of the glymphatic system].”
The glymphatic system was first identified in 1985, in slices of brain tissue from cats and dogs that had been previously perfused with a protein tracer. Others tried to replicate the results in live animals, by carving out 'windows' in the skull, through which they could eavesdrop on brain activity. But this treatment reduced the pressure inside the skull, which dramatically impeded fluid movement through the system. They could not confirm the anatomical data, and so the initial findings were dismissed.
Today, these limitations have been overcome, and researchers now have a variety of methods for imaging the glymphatic system. Mark Lythgoe and his colleagues at UCL's Centre for Advanced Biomedical Imaging are focused on developing new methods for imaging the brain clearance pathway in Alzheimer's.
One of these is based on diffusion tensor imaging (DTI), a neuroimaging technique that detects the flow of water molecules and is widely used to visualize the brain's white matter tracts. Until now, such methods relied on the injection of a chemical called a contrast agent to enhance the signal being detected. The new method does not require a contrast agent, however, and so is completely non-invasive. “Once you can isolate this signal, you can start to do things with it,” said Lythgoe. “You can look at the magnitude of movement, and you can sensitize it to the direction of water movement as it flows through the various feeding channels.”
Lythgoe concluded by saying that the continuing development of non-invasive imaging methods will be vital to learning more about the structure and function of the glymphatic system. “The big question now is: How do we modulate glymphatic clearance?” he said. ≈©
This article was published by the Dana Foundation, November 21, 2018.
MOHEB COSTANDI is a molecular and developmental neurobiologist turned freelance science writer based in London. He writes the Neurophilosophy blog, hosted by The Guardian, and is the author of Neuroplasticity (MIT Press, 2016) and 50 Human Brain Ideas You Really Need to Know (Quercus, 2013).