A peek inside human brain shows a way it cleans out waste
Why do we sleep? Science has not answered that yet, but several reasons have been proposed. It gives time for physical rest, of course. It might allow the brain to reorganize thoughts and memories. Sleep also helps us to remain alert and capable of clear reasoning. Many more ideas abound. But new research also says it allows the brain to physically clean itself. How is that done?
The circulatory system in the body is the collection of veins and arteries that carries red blood cells (for oxygen), white blood cells (for defense against bacteria and viruses), and platelets (which clot wounds to stop bleeding). Arteries carry blood away from the heart; veins carry it back. Part of the job of this system is to send blood for cleaning, too, as explained below:
- In the lungs, fresh air is exchanged to remove carbon dioxide and fill blood with oxygen.
- In the kidney, waste products (like urea) are removed, and so are extra water, and some toxins.
- In the liver, blood is detoxified of harmful substances (like drugs or alcohol)
Left, whole body circulation; right, brain circulation (red: arteries, blue: veins)
Another system in the body is called the lymphatic system, which is made of several organs (like the thymus, tonsils, and spleen) and lymph nodes. They are all connected with a different system of tubes that run near the circulatory system and sometimes intersect with it. The lymphatic system has three basic functions:
- deliver white blood cells to the body to fight infection,
- carry nutrients to cells and tissues, and
- serve as a drainage system for fluids leaking out of capillaries when the surrounding tissue does not absorb it. This clear liquid is called lymph.
How the lymphatic system (green) collects and flushes the body (Current Biology, 2021)
About 20 liters of fluid from the blood seeps from capillaries (where arteries and veins join) and into the surrounding tissues. It's like a leaky garden hose under the soil. This fluid carries nutrients and oxygen. But 17 liters of that flows back into the capillaries to carry out waste and carbon dioxide. The remaining 3 liters is picked up by the lymphatic system, like a series of drainage pipes getting bigger and bigger until they reach the lymph node. It is then deposited in the bloodstream for further removal.
If you look at the diagram below, you can see that there appears to be no lymphatic system in the brain. Lymph channels in the head are actually on the back but not surrounding the skull. If you compare the diagram with an earlier one, you can see there is a blood circulation system around the brain, though, because it needs oxygen. 
Normally, the blood vessels that surround the brain exchange oxygen for carbon dioxide when they cross the capillary cell wall (at the point where arteries meet veins). Bigger molecules can pass into the brain but do so through protein filter seals called tight junctions built right into the capillary wall cells. But they are so tight that they block germs from entering the brain. This blood-brain barrier is all over the brain except in certain areas like the pituitary gland which needs direct access to the bloodstream to deliver hormones.
Body diagram modified from Wikipedia; head diagram from SaintLukesKC.org
Normally, the blood vessels that surround the brain exchange oxygen for carbon dioxide when they cross the capillary cell wall (at the point where arteries meet veins). Bigger molecules can pass into the brain but do so through protein filter seals called tight junctions built right into the capillary wall cells. But they are so tight that they block germs from entering the brain. This blood-brain barrier is all over the brain except in certain areas like the pituitary gland which needs direct access to the bloodstream to deliver hormones.
Comparison of cross-sections of blood vessels in the body and the brain. (From YouTube)
So, aside from carbon dioxide, what needs cleaning in the brain that needs a special system of drainage?
The brain is composed of living cells, and like other cells in the body, they need nourishment and excrete waste products. A common waste is lactate from sugar metabolism. A not-so-common waste is called amyloid beta peptides (Aβ). These fragments of protein come from a bigger molecule (APP) that is part of the cell membrane of oligodendrocytes (cells which wrap around and make up the insulating myelin sheath around the long part of a nerve cell).
Two images of oligodendrocytes wrapping around nerves to make myelin coatings
The part of APP sticking out of the membrane is sliced off by 2 enzymes leaving the Aβ to float around outside the cell. They can be further broken down and (a) removed or (b) join with metal ions to create groups that may eventually form plaques found on brain cells of senile patients. They interfere with nerve cell signaling, trigger inflammation, and contribute to cognitive decline and memory loss. So, it is important to flush these out.
Researchers at the Oregon Health & Science University have just discovered a third system of channels in the body; it drains waste from around brain cells like the lymphatic system does elsewhere in the body. It is called the glymphatic system. It is composed of a special type of glial cell (a type of nerve cell that does not conduct impulses, but instead it provides support, protection, and nourishment to nerve cells that do conduct impulses).
Notice in the picture above how the glymphatic system tracks with the blood system in the first picture on this page.
In a 2019 study by David Holtzman, his team showed how tau protein gets cleared from normal mice. The tau protein normally helps support a cell structure, but abnormal tau molecules can lead to plaques like APP. Follow the blue dye-stained normal tau in this mouse brain to see how it should be removed and is within 72 hours.
Even before the glymphatic system was discovered, researchers still noticed that when mice slept or were anesthetized, drainage was better than when the mice were awake.
At the time, just 2 years before the drainage system in mice was discovered, scientists did not know how chemicals like amyloid beta were removed from the brain, but the key point was that it took place faster and better when the animals were sleeping. In fact, when they were awake, more amyloid beta was made, leading the mice to stay awake longer in a vicious circle.
Formation of amyloid beta peptides (Modified from Redox Biology, 2018)
Amyloid plaques (orange) on nerves (blue) (from Alzheimer's Disease Research)
Researchers at the Oregon Health & Science University have just discovered a third system of channels in the body; it drains waste from around brain cells like the lymphatic system does elsewhere in the body. It is called the glymphatic system. It is composed of a special type of glial cell (a type of nerve cell that does not conduct impulses, but instead it provides support, protection, and nourishment to nerve cells that do conduct impulses).
It gets it name by combining the nerve cell name and the draining action like lymph:
Glial + Lymphatic-like = Glymphatic
(left) Dark blue shows the lymphatic system in the brain using an MRI scan with blue dye.
(right) Cross section of brain tissue showing lymph vessel (LV) blood vessels (BV).
(Images from YouTube of Dr. Daniel S. Reich at NIH’s National Institute of Neurological Disorders and Stroke)
Notice in the picture above how the glymphatic system tracks with the blood system in the first picture on this page.
What gave scientists hope that humans would have this drainage system came about in 2015 when mice were examined during research on Alzheimer's disease. A similar system was found in zebrafish in 2019 when researchers were simply investigating how the lymphatic system overall develops in those fish. They are the fish equivalent of white mice and are used a lot in genetic studies.
Left, zebrafish; Right, mouse
Brains with networks of lymphatic systems (in green)
(from Hogan and Bower, 2021)
In a 2019 study by David Holtzman, his team showed how tau protein gets cleared from normal mice. The tau protein normally helps support a cell structure, but abnormal tau molecules can lead to plaques like APP. Follow the blue dye-stained normal tau in this mouse brain to see how it should be removed and is within 72 hours.
Blue tau protein gets drained out by the lymphatic system of a mouse brain (Molecular Neurodegeneration, 2019)
Even before the glymphatic system was discovered, researchers still noticed that when mice slept or were anesthetized, drainage was better than when the mice were awake.
Drainage of amyloid beta from mouse brains (Science, 2013)
At the time, just 2 years before the drainage system in mice was discovered, scientists did not know how chemicals like amyloid beta were removed from the brain, but the key point was that it took place faster and better when the animals were sleeping. In fact, when they were awake, more amyloid beta was made, leading the mice to stay awake longer in a vicious circle.
Now, we know more about the plumbing system. Moreover, sleeplessness caused by insomnia and even short bursts of waking in cases of apnea may aggravate the process and eventually lead to dementia or death unless changes are made in a person's sleep schedule. We know more about why now. It's not just to rest our minds, but to clear out harmful materials.
