Optimizing the Brain’s “Washing Machine” to Clean Up Alzheimer’s

Sometimes, the proteins in the body stop doing their jobs. They turn into polluting plaques, tangles and globs that can build up in the brain. This clutter disrupts brain cells, causing inflammation, and eventually, cell death. To help clean house, the brain does have a washing machine, which disposes of this protein clutter during sleep. If this washing machine breaks down, it could lead to neurodegenerative brain diseases like Alzheimer’s. It’s called the glymphatic system.

How does the glymphatic system work? To wash dirty clothes, the washing machine mixed together water and detergent. Then, the washing machine drains away the dirty water through a series of pipes. In the human body, that water and detergent is cerebrospinal fluid — a clear liquid that nourishes, protects, and cleans the brain and spinal cord — the detergent of the central nervous system. It cleans everything out, then drains through a series of tunnels called lymphatic vessels, taking plaques and toxic proteins away with it. The lymphatic vessels contain a lot of immune cells and machinery needed to dispose of the toxic proteins. Eventually, the clean fluid is recycled back into the body. 

But, when this process isn’t working well, it may lead to some very messy problems. In Alzheimer’s disease for example, some of the proteins in the body stop doing their jobs, turning into polluting plaques, tangles and globs that build up in the brain. The result: Impaired cognitive function, cell death, and too much inflammation.

As scientists have studied this process, in hopes of understanding how to prevent or stop the progression of diseases like Alzheimer’s, they’ve learned that even one night of sleep deprivation increases levels of Alzheimer’s hallmark protein, beta-amyloid, in the brain. Meanwhile, getting too much or too little sleep have also been linked to a higher risk of Alzheimer’s and other dementias.

Cleaning the brain while we sleep

Until recently, neuroscientists thought that the body’s immune system wasn’t able to get to the brain. When it came to diseases like Alzheimer’s, inflammation wasn’t even considered a part of the equation. So in the 1970s, when researcher Helen Cserr found a system of tunnels that allowed immune cells into the brain to help clear waste, she was ostracized and eventually left research. Cserr died in 1994 of a brain tumor. 

Three decades later, Maiken Nedergaard, a professor of neurology at the University of Rochester Medical Center in New York proved her right — “rediscovering” the glymphatic system — the a series of tunnels which disposes of protein clutter and debris during sleep.

Nedergaard popularized this comparison of the glymphatic system to a dishwasher — a metaphor that’s become popular among scientists across the field.

“We get this buildup of this grime, this beta-amyloid stuff on our plates, which you can think of as the nerve cells in our brain,” Roger Wong, an assistant professor at SUNY Upstate Medical University told Being Patient in a recent LiveTalk. “During the nighttime, when we’re sleeping, all of this is drained away along with the beta-amyloid.” 

How does the glymphatic system clear out beta-amyloid and other toxic proteins?

A key protein involved in this system is called Aquaporin-4 (AQP4). It serves as the drain in the washing machine metaphor. Changing the size or shape of this drain affects how well the glymphatic system works.

Scientists have discovered that some variants of the AQP4 gene appear to be more efficient than other variants at draining clutter from the brain: They are related to different speeds of cognitive decline. 

For example, a person who gets nine hours of sleep but has an inefficient version of AQP4 might still have a lot of beta-amyloid buildup. This might mean they are at a higher risk of developing Alzheimer’s, or that they might experience a faster rate of cognitive decline as they age than someone with a different AQP4 variant. 

So, what if we could swap out the parts of the brain’s washing machine to make them all super-efficient at clearing the protein junk that leads to neurodegeneration?

Turbocharging the glymphatic system

While the research into the glymphatic system is still in its early stages, scientists have recently made some exciting developments, discovering a few methods to boost the power of the glymphatic system. Fiddling with the AQP4 gene is one of them.

Researchers, including a team at the University of Niigata Japan, are testing drugs that, like plumbers, can help open up the AQP4 protein allowing more cleaning fluid to pass through, for more efficient cleaning. This means the brain can run more “wash cycles” during sleep. 

Another strategy involves infusing intravenous saline — which causes the system to speed up the wash cycle. Researchers at the University of Helsinki are hoping to test this strategy in clinical trials.

In research labs from Finland to Japan, scientists are hard at work testing the glymphatic system. A combination of drugs and intravenous saline could one day help treat or reduce the risk of developing Alzheimer’s disease.