Clear Your Mind

By Carolyn Keating

March 6, 2018

 

Everyone generates garbage. To prevent garbage from accumulating in our homes and cities, we get rid of our waste by throwing scraps down the garbage disposal or flushing the toilet, and let the pipes of our community sewage systems take care of the rest. It turns out that our bodies also generate garbage on a much smaller scale. This biological garbage consists of by-products created by our cells as they carry out their day-to-day functions, and must also be disposed of. Much like the sewage systems in place in our towns, the body also uses a similar set-up to dispose of its garbage. So what does the body’s sewage system look like?

You’re probably familiar with the cardiovascular system: the heart pumps blood through vessels around the body in order to deliver nutrients and oxygen to tissues. You may be less familiar with the lymphatic system, another network of vessels that run throughout the body. This open system functions to collect excess fluids from body tissues and return them to the bloodstream. Along with fluid, the lymphatic system also transports waste generated by cells, as well as any invading bacteria or viruses (you may have noticed lumps on your neck that feel swollen when you’re sick; that’s because these “lymph nodes” are involved with the immune system as well as the circulatory system).

Oddly enough, while the lymphatic system has been known to doctors and scientists for centuries, until 6 years ago it was thought to be completely absent in the brain since there were no conventional lymphatic vessels. But in 2012, scientists at the University of Rochester in New York made headlines when they reported finding a unique glymphatic system in the brain1.

 

What’s the Glymphatic System?

“Glymphatic” is a combination of the words “lymphatic” and “glia”. Glia are the cells in the brain that aren’t neurons. There are many different kinds which mostly function to support neurons in various ways, including supplying nutrients, insulating axons, and providing physical support. The primary glial cell involved with the glymphatic system is called an astrocyte. These star-shaped cells extend many processes, some of which reach out to enclose blood vessels passing through the brain.

BBB
Figure 1: The blood-brain barrier. Blood is surrounded by endothelial cells (blue) that form vessels. In the brain, vessels are also surrounded by pericytes (purple), and more importantly, astrocytic processes termed end-feet (green). You can see that there is some space between the vessel and the end-feet.

These astrocyte “end-feet” completely surround blood vessels to help regulate what can or cannot pass through from the blood to the brain, forming the blood-brain barrier (Figure 1). The astrocyte end-feet aren’t directly touching the blood vessels, however. There’s some space between the vessels and the glia, forming a tube that can be filled with fluid. The astrocytes let this fluid pass through their end-feet, allowing it to exchange with the extracellular fluid that surrounds neurons and other cells. This glymphatic fluid moves through the brain, picking up any waste generated by the cells, before it follows veins out of the brain and eventually meets up with the traditional lymphatic system in the head and neck2.

 

How did scientists figure it out?

Researchers performed some really cool experiments to discover the glymphatic system. They took advantage of the fact that the brain isn’t just sitting inside the skull, it’s actually floating in a liquid called cerebro-spinal fluid, or CSF. Scientists thought this fluid might be responsible for clearing out the waste in the brain. So they started by injecting different sized particles attached to markers they could visualize into the CSF of anesthetized mice. Then they drilled a tiny hole into the (still anesthetized) mice’s skulls, and placed them under a special microscope that allowed them to peer into the top layers of the animals’ brains. This setup let them monitor whether or not the CSF moved into and out of the brain in real time! Remarkably, scientists saw that the particles they had put into the CSF surrounding the brain traveled along the space between arteries and the astrocytes forming the blood-brain barrier, diffused into the brain, and then back out in the space between astrocytes and veins1 (Figure 2).

Figure 2: Video from the University of Rochester team that discovered the glymphatic system. The top left shows what the researchers actually saw under the microscope when they injected green-colored particles into the CSF of mice and watched them travel along blood vessels. The cartoons on the top right illustrate how the CSF traveled down into the brain in the space next to blood vessels. The cartoon on the bottom demonstrates how the CSF passes through the brain to pick up waste products such as amyloid-β, then exits along veins.

Around the same time as this discovery, other researchers were re-examining the brain for signs of traditional lymphatic vessels like the ones found throughout the body. Scientists first found evidence of mouse nervous system lymphatic vessels in the dura mater, a leather-like protective covering between the brain and the skull3. That finding prompted other teams to look for the vessels in humans, and last year MRI scans revealed lymphatic vessels in the dura mater of living people for the first time ever4!

 

Cool, but why does this system matter?

The discovery of a lymphatic-like system in the brains of animals and humans is more than just an interesting finding to people who like to study anatomy. The glymphatic system seems to play a role in neurodegenerative diseases in which clumps of proteins build up in the brain, such as Alzheimer’s disease (AD). Amyloid-β, one of the proteins that builds up in AD, was found to be cleared from the brain through the glymphatic system.  As we age (and when there is inflammation in the brain, such as during neurodegenerative diseases), the glymphatic system becomes less effective at clearing waste. In turn, more amyloid-β builds up in the brain, causing more inflammation and further impairing the glymphatic system5.

But it’s not all bad news. A recent study has linked drinking low to moderate amounts of alcohol (about two and half drinks per day) to improved glymphatic activity. Additionally, the system is basically only active when we’re asleep, clearing out all the waste produced while we’re awake. So the next time someone gives you a hard time for wanting to go to happy hour or take a nap, just tell them you’re cleaning out your brain!

 

 

Sources:

  1. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci. Transl. Med. 4, 147ra111 (2012).
  2. Jessen, N. A., Munk, A. S. F., Lundgaard, I. & Nedergaard, M. The Glymphatic System: A Beginner’s Guide. Neurochem. Res. 40, 2583–2599 (2015).
  3. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
  4. Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife 6, (2017).
  5. Simon, M. J. & Iliff, J. J. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. Biochim. Biophys. Acta – Mol. Basis Dis. 1862, 442–451 (2016).

 

Images:

Figure 2: https://commons.wikimedia.org/w/index.php?title=File%3AVideo_schematic_of_glymphatic_flow.ogv

 

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