It’s odd how long the news of an important discovery can take to reach its audience. Take the case of the Glymphatic System by which Cerebrospinal Fluid (CSF) cleans out debris from the brain. A knowledgeable and current website says that “CSF flows within and around the brain and spinal cord to help cushion it from injury.” There is no mention of the incredibly important role that CSF plays in the Glymphatic System.
Way back in 2012 “A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β” was published trumpeting the discovery by University of Rochester researchers of a previously unknown mechanism for clearing the brain. It turns out that the brain has a way of allowing the CSF to flow through the functional tissue in the brain. By functional we mean the neurons and glial cells and not the structural portions. The functional portion of an organ is known as the parenchyma and when that is damaged in the brain the result is often a loss of cognitive ability.
What the University of Rochester researchers discovered was one of the critical processes by which the brain protects itself from accumulated damage and maybe even from the kind that leads to Alzheimer’s.
CSF moves through the regular fluid channels, but also manages to move through the tight spaces between cells and clear away extracellular proteins including the soluble form of amyloid-beta and tau. It does this in part by moving deeper into tissue by following the path of penetrating arteries. From there two mechanisms push it along until it meets up with blood vessels and follows their pathway out. The researchers named this the glymphatic system or pathway.
In the circulatory system (grossly simplified) the heart pumps oxygenated blood throughout the body via arteries. After use by cells the deoxygenated blood is returned to the lungs by veins.
This blood transport of oxygen and nutrients happens in the brain as well, but what wasn’t known was that the CSF travels alongside the arteries and the tiny offshoots called para-arterial pathways to get deep into the brain. Instead of reaching the end of the line and pooling, the CSF is grabbed by cells called astroyctes and moved along from cell to cell. As it moves through the space between cells it picks up waste products and carries them along. On the other side of this space the CSF meets up with veins that are transporting the deoxygenated blood away from the brain. Just as they followed the arterial channel into the brain, the CSF travel out by following the paravenous channels (small side branches of the venous system). On this final leg of the journey waste products are transferred to the blood and are carried away from the brain. Ultimately the waste products end up in the liver where they are degraded.
Into The Weeds
One of the ways that fluid moves about in the central nervous system (CNS) is with the assistance of proteins called aquaporins that move water from one side of the cell membrane to the other. There are about 7 aquaporins within the CNS, but only 3 in the brain and spinal cord. Astrocytes in the brain have the specific protein aquaporin-4 (AQP4) which plays an outsized role in the glymphatic system as it, along with arterial pulsing, move the CSF through the tight-packed cellular space.
Just to make sure that AQP4 was critical to the process, the researchers checked using mice with the AQP4 gene deleted and found that the CSF flow was slowed and there was a roughly 70% reduction in waste product clearance. Furthermore, the knockout mice had suppressed clearance of soluble amyloid β.
The following year saw two studies on the glymphatic system. “Brain-wide pathway for waste clearance captured by contrast-enhanced MRI” demonstrating that the glymphatic system could be viewed in action using contrast-enhanced MRI. They also fine-tuned observations of the glymphatic pathways (hint: “external brain surface arteries, such as the basilar artery, communicating arteries of the Circle of Willis, and olfactory arteries, constitute a rapid transport pathway for CSF within the wider subarachnoid space and ultimately the brain proper). The second study from 2013 “Sleep drives metabolite clearance from the adult brain” added the important details that the interstitial space expands by as much as 60% when we sleep and they observed a “striking increase” in the waste clearing effects (including amyloid-beta) of the glymphatic system during periods of sleep.
In 2015 “The Effect of Body Posture on Brain Glymphatic Transport” showed that sleep position makes a difference. Waste removal, including Aβ, was most efficient when you sleep on your side or back and not on your front.
Already in the first month of 2018 we have two more important revelations about the glymphatic system. Voluntary running enhances glymphatic influx in awake behaving, young mice – this looks at the effects of exercise and (surprise surprise) the effects are positive. Previous studies indicated that older mice who exercised had increased glymphatic activity while sleeping. This study shows that young mice also benefit and even while awake. Now I have to update my article on the benefits of exercise.
The other recent report already this year is that moderate levels of alcohol consumption 1 to 2.5 drinks per day enhances the glymphatic system. “Beneficial effects of low alcohol exposure, but adverse effects of high alcohol intake on glymphatic function” emphasizes that alcohol consumption produces a J curve such that a little is good, but the more you consume the worse off you are. It’s like the adage that two aspirin will cure your headache, but taking the whole bottle will kill you. It’s the same with alcohol, just a lot slower.
Mice on a 30 day exposure to moderate levels of alcohol showed a roughly 5% increase in clearance of florescent tracer used by the researchers to track movement of CSF through the brain.
They also found that moderate alcohol consumption decreased GFAP in astrocytes. Conversely, chronic, moderate to heavy, use of alcohol resulted in hypertrophic GFAP-positive astrocytes much like those seen in Traumatic Brain Injury (TBI). TBI also results in a nearly 60% reduction in glymphatic processes and has a very high correlation with future dementia.
The more we know about Alzheimer’s and dementia the greater the number of interconnections we find. The glymphatic pathway discovered in 2012 has shown not just a novel method for the clearance of waste from the brain, but continuing research is showing that exercise, sleep, and moderate alcohol consumption enhance that waste removal process.
The positive effects of exercise, sleep, and moderate alcohol consumption on our brains and on cognition is real and measurable. The exact mechanisms for these positive effects is less clear, but the connection to the glymphatic system gives us at least some explanation for why they work. Conversely, the negative effect of TBI on the glymphatic pathway may help to explain why it so often leads to Alzheimer’s.
Sleep well and get some exercise. I’ll leave the alcohol thing up to you.