Did you know you have your own personal internal plumbing system that cleanses your brain of toxic wastes?
Fun Fact: The human brain weighs about three pounds, which is about 2 percent of the average adult body mass. Its cells consume 20 to 25 percent of the body’s total energy and in the process, excessive amounts of potentially toxic protein wastes and biological debris are generated. Each day, the adult brain eliminates a quarter of an ounce of worn-out proteins that must be replaced with newly made ones. This is the equivalent to the brain’s own weight in waste, over the course of a single year.
To continue to function properly, the brain must have some way of flushing out this debris. The most finely tuned organ, capable of producing thoughts and actions surely must have an efficient waste disposal system. But until very recently, this system remained a mystery.
That is, until roughly seven years ago, scientists began to study how the brain eliminates proteins and other wastes. They also began to explore how interference with that process might cause the cognitive problems experienced in numerous neurodegenerative diseases, due to the eventual accumulation of protein debris in and around cells.
In most regions of the body, a network of intricate fluid-carrying vessels, known as the lymphatic system, eliminates protein waste from tissues.
Waste-carrying fluid moves throughout this network between cells, collecting in small ducts that then lead to larger ones and eventually into blood vessels. This duct structure also provides a path for immune defense, because lymph nodes, a receptacle of infection-fighting white blood cells, populate ducts at key points throughout the network. Yet, for over a century, neuroscientists believed the lymphatic system did not exist in the brain or spinal cord.
“The brain’s blood vessels are surrounded by what are called perivascular spaces. They are doughnut-shaped tunnels that surround every vessel. The inner wall of each space is made of the surface of vascular cells, mostly endothelial cells and smooth muscle cells. But the outer wall is unique to the brain and spinal cord and consists of extensions branching out from a specialized cell type called the astrocyte.
Astrocytes are support cells that perform a multitude of functions for the interconnected network of neurons that relay signals throughout the brain. The astrocytes’ extensions—astrocytic end feet—completely surround the arteries, capillaries and veins in the brain and spinal cord. The hollow, tubelike cavity that forms between the feet and the vessels remains largely free of obstructions, creating a spillway that allows for the rapid transport of fluid through the brain.”
Scientists knew about the the perivascular space but had not identified any specific function for it. In the late 1980’s, Neuroscientist Patricia Grady described perivascular fluid flows, but the significance of her finding was not discovered until many years later. Her report stated that large proteins injected into the cerebrospinal fluid (CSF) could also be found in the perivascular spaces of both dogs and cats. At the time, other groups could not replicate her findings, and not knowing the significance of what such an observation might be, research did not proceed any further.
Scientists became immediately interested in the multiplicity of the water channels, built from a protein called aquaporin-4, and their positions facing the blood vessel walls. The density of these water channels was comparable to that of those in the kidney, an organ whose primary duty is to transport water. Interest peaked when they took a closer look and found that the vascular endothelial cells bordering the perivascular space lacked these channels. Thus, fluid could not be moving directly from the bloodstream into brain tissue, and instead, the liquid had to be flowing between the perivascular space and into the channels, thereby gaining access to the brain tissue.
So… What does this mean?
“We asked whether the perivascular space might constitute a neural lymphatic system. Could it perhaps provide a conduit for cerebrospinal fluid? Arterial pulsations might drive the CSF through the perivascular space. From there, some of it could enter astrocytes through their end feet. It could then move into the area between cells and finally to the perivascular space around veins to clear waste products from the brain.
Along with our laboratory members Jeff Iliff and Rashid Deane, we went on to confirm this hypothesis. Using chemical dyes that stained the fluid, combined with microscopic techniques that allowed us to image deep inside live brain tissue, we could directly observe that the pumping of blood propelled large quantities of CSF into the perivascular space surrounding arteries. Using astrocytes as conduits, the CSF then moved through the brain tissue, where it left the astrocytes and picked up discarded proteins.
The fluids exited the brain through the perivascular space that surrounded small veins draining the brain, and these veins in turn merged into larger ones that continued into the neck. The waste liquids went on to enter the lymph system, from which they flowed back into the general blood circulation. They combined there with protein waste products from other organs that were ultimately destined for filtering by the kidneys or processing by the liver.
When we began our research, we had no idea that astrocytes played such a critical role in the brain’s counterpart of a lymphatic system. Additional proof came when we used genetically engineered mice that lacked the aquaporin-4 protein that makes up the astrocytes’ water channels. The rate of CSF flow entering the astrocytes dropped by 60 percent, greatly slowing fluid transport through their brain.”
Scientists have now traced a complete pathway within the brain for the cleansing fluids to effectively sweep away waste products. They named the discovery “The Glymphatic System”. The newly coined word combined the words “glia”—a type of brain cell of which the astrocyte is one example—and “lymphatic,” thus referencing this newly discovered function of the brain’s glial cells.
As the importance of the glymphatic system’s role was realized, scientists immediately wondered whether proteins that build up in the brain in neurodegenerative diseases might be typically washed out along with other cellular wastes in a healthy brain. They focused on a protein linked to Alzheimer’s called beta-amyloid, which had previously been thought to be cleared under normal circumstances by degradation or recycling processes which take place within all brain cells. In Alzheimer’s, aggregates of beta-amyloid form amyloid plaques between cells that may contribute to the disease process. Scientists found that in a healthy brain, the beta-amyloid is cleared by the glymphatic system.
A symptom that accompanies Alzheimer’s and other neurodegenerative diseases provided the scientists with a hint of how to proceed. Many patients with Alzheimer’s experience sleep disturbances long before their dementia becomes apparent. In older individuals, sleep becomes more fragmented and shallow and lasts a shorter amount of time. Epidemiological studies have shown that patients who reported poor sleep in middle age were at greater risk for cognitive decline than control subjects when tested 25 years later.
“Even healthy individuals who are forced to stay awake exhibit symptoms more typical of neurological disease and mental illness—poor concentration, memory lapses, fatigue, irritability, and emotional ups and downs. Profound sleep deprivation may produce confusion and hallucinations, potentially leading to epileptic seizures and even death. Indeed, lab animals may die when deprived of sleep for as little as several days, and humans are no more resilient. In humans, fatal familial insomnia is an inherited disease that causes patients to sleep progressively less until they die, usually within 18 months of diagnosis.”
Scientists then theorized that the sleep difficulties of dementia might not just be a side effect of the disorder but be a contributor to the disease process itself. If the Glymphatic System cleared beta-amyloid during sleep at a higher rate than when awake, it’s possible the poor sleeping patterns of patients with neurodegenerative disorders could contribute to a worsening of the disease. Initial experiments were performed on anesthetized mice and scientists further speculated that the fast fluid flows noted were not necessarily what might be anticipated in an awake and active brain, which would be subject to other demands in its typical functioning.
The idea was tested by Lulu Xie and Hongyi Kang, who trained mice to sit still underneath a microscope to capture images of a tracer chemical in the CSF using an imaging technique called two-photon microscopy. They then compared how the tracer moved through the Glymphatic system in awake mice versus sleeping mice. Don’t worry- the tests were neither invasive nor painful and the mice remained quiet and compliant, so much so that they often fell asleep while being imaged. They were then able to image inflows of CSF in a particular area of the same mouse brain during both sleep and wakefulness.
As it turned out, CSF in the Glymphatic System fell dramatically while the study mice were awake. Within minutes after the onset of sleep or the effects of anesthesia, however, influxes of the fluid increased significantly. In a collaboration with Charles Nicholson of NYU, scientists found that the brain’s interstitial space—the area between cells through which glymphatic fluid flows on its way to perivascular spaces around veins—rose by more than 60 percent when mice fell asleep. Scientists now believed that the flow of glymphatic fluid increases during sleep because the space between the cells expands, which helps to push fluid through the brain tissue.
Research also revealed how the rate of fluid flow is controlled. A neurotransmitter, or signaling molecule, called norepinephrine appeared to regulate the volume of the interstitial area and consequently the pace of glymphatic flow. Levels of the norepinephrine rose when mice were awake and were insufficient during sleep, implying that transient, sleep-related dips in norepinephrine led to enhanced glymphatic flow.
Could sleep deprivation precipitate neurodegenerative disease?
Experiments that were conducted in mice showed that during sleep, the Glymphatic System did indeed remove beta-amyloid from the brain with remarkable efficiency: its clearance rate more than doubled with sleep. On the other hand, mice genetically engineered so that they lacked aquaporin-4 water channels in astrocytes demonstrated markedly impaired glymphatic function, clearing 40 percent less beta-amyloid than control animals.
Scientists know remarkably high percentage of beta-amyloid removed challenged the widely held idea that brain cells break down all their own wastes internally.
So far these investigations have not moved beyond basic research labs.
Drug companies have yet to consider antidementia therapies that would physically remove amyloid and other toxic proteins by washing out the brain with glymphatic fluids. But maybe they should. New strategies are desperately needed for a disease that costs the U.S. health care system $226 billion annually. A number of clinical trials for Alzheimer’s are under way, though no drug in development has yet demonstrated a clear-cut benefit.
A pharmaceutical that regulates the Glymphatic System by increasing the rate of CSF flow during sleep could literally flush amyloid out of the brain. A treatment used for a well-known neurological syndrome provides a clue that this approach might work. Normal-pressure hydrocephalus, an illness typically seen in the elderly, is a form of dementia in which excessive CSF accumulates in the hollow central brain cavities, the cerebral ventricles. When a procedure called lumbar puncture removes the fluid by draining it out, patients often exhibit remarkable improvements in their cognitive abilities. The basis for this observation has long been a mystery. Our research suggests that restoring fluid flows through the Glymphatic System might mediate the restoration of cognition in these patients.
The sole knowledge of the Glymphatic Systems suggests fresh ideas for diagnosing Alzheimer’s and other neurological conditions. A recent study by Helene Benveniste of the Stony Brook School of Medicine has shown that standard magnetic resonance imaging may allow tests of glymphatic flow designed to predict disease progression in patients suffering from Alzheimer’s or related dementias. It could even foretell the ability of patients with traumatic brain injuries to recover. The Glymphatic System may also prove to be a rich area for gaining a basic understanding of how the brain works.
Fascinatingly, fluids moving through the Glymphatic System may do more than remove wastes; they may deliver various nutrients and other cargo to brain tissue. A new study showed that glymphatic channels deliver glucose to neurons to provide energy. Further studies are now investigating whether white matter, the insulation-like sheathing around neurons’ wire-like extensions, called axons, may rely on the Glymphatic System for delivery of both nutrients and materials needed for maintaining the cells’ structural integrity. Such studies promise to elucidate the many unexpected roles of the Glymphatic System in the daily life—and nightlife—of the brain.
In the meantime, adequate sleep is imperative for the Gylmphatic System to perform its job properly.
The brains cells consume 20 to 25 percent of the body’s total energy and in the process, large amounts of potentially toxic protein wastes and biological debris are generated.
- In most regions of the body, a network of intricate fluid-carrying vessels, known as the lymphatic system, eliminates protein waste from tissues.
- Scientists have now traced a complete pathway within the brain for the cleansing fluids to effectively sweep away waste products. With testing using dye, scientists found that the fluids exited the brain through the perivascular space that surrounded small veins draining the brain, and these veins in turn merged into larger ones that continued into the neck. The waste liquids went on to enter the lymph system, from which they flowed back into the general blood circulation. They combined there with protein waste products from other organs that were ultimately destined for filtering by the kidneys or processing by the liver.
- They named the discovery “The Glymphatic System”. The newly coined word combined the words “glia”—a type of brain cell of which the astrocyte is one example—and “lymphatic,” thus referencing this newly discovered function of the brain’s glial cells.
- Research also revealed how the rate of fluid flow is controlled. A neurotransmitter, or signaling molecule, called norepinephrine appeared to regulate the volume of the interstitial area and consequently the pace of glymphatic flow. While performing tests on lab mice, scientists discovered that the levels of the norepinephrine rose when test mice were awake and were insufficient during sleep, implying that transient, sleep-related dips in norepinephrine led to enhanced glymphatic flow.
- Adequate sleep is imperative for the Gylmphatic System to perform its job properly.
Disclaimer: This writing is not the work or ideas of my own. I just find this study compelling and beneficial to any who would like to improve their brain health.