Tag Archives: glymphatic

How Sleep “Cleans” Your Brain and Fends Off Alzheimer’s Disease

Sleep: we spend nearly a third of our lives doing it, yet only recently have we begun to understand its true purpose. You’ve probably read countless articles about how getting enough sleep is important for preventing a variety of diseases, including diabetes, depression, and even Alzheimer’s. However, while strong correlations have existed for decades, until recently there was still little evidence to show why we sleep or how it fends off disease.

As some of you may know, I’m currently living in Switzerland, where I’m conducting research at EPFL over the summer. My research is on the connection between sleep deprivation and Alzheimer’s disease, so for me it’s especially important to help others understand why sleep is so important for your brain’s overall health. A few recent breakthroughs in sleep science research have revolutionized the field and brought about an exciting new era of neuroscience, particularly for Alzheimer’s disease research.

The Brain: A Dumping Ground for Neuronal Waste

While you’re awake, the 100 billion neurons in your brain are hard at work. Through an incredibly complex network of connections and signals, your neurons keep your heart pumping, your muscles moving, and your attention focused on the task at hand. Every time a neuron fires a signal, it undergoes a series of chemical reactions to produce neurotransmitters, which it uses to communicate with other cells. These reactions also produce waste byproducts that need to be disposed of. The neuron packages the waste into vesicles and excretes them into the fluid that surrounds cells in the brain. How these waste products were cleared from the fluid remained a mystery for a long time. More on that in a bit.

These waste products used to not be seen as particularly important to study. But in 2005, a group of scientists came up with a crazy idea that would end up shaking the foundations of Alzheimer’s research: what if amyloid-beta is one of these byproducts of neuronal activity? As a bit of background, amyloid-beta is a protein that forms sticky plaques in the brains of people with Alzheimer’s disease. At large enough sizes, these plaques become toxic to neurons, resulting in neurodegeneration. This is believed to be one of the main driving forces behind the development of Alzheimer’s disease. At the time, we  knew that amyloid-beta came from neurons, but were unsure what caused the neurons to produce it or how to stop them.

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This is what an amyloid-beta plaque looks like inside a real brain. Image Source

The researchers tested their hypothesis using mice genetically engineered to produce human amyloid-beta. They surgically implanted an electrode in the mice’s brains, which was used to measure the neurons’ activity levels. They also implanted a microdialysis probe, which sampled the mice’s brain fluid periodically to monitor levels of amyloid-beta. When the researchers electrically stimulated the mice’s brains, causing neurons to become highly active, they saw an abrupt increase in amyloid-beta levels in the area of stimulation. Conversely, when they used drugs to decrease neuronal activity, amyloid-beta levels dropped.

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This is one of the figures from that study. Panel A shoes the mice’s EEG activity (a measure of neuronal firing) before and after the electrical stimulation. Panel B shoes the immediate increase in amyloid-beta levels after stimulation, while Panel C shoes the decrease after drug treatment to reduce neuronal activity.

The results of this landmark study were published in the journal Neuron and have since been cited hundreds of times by other papers. Many other studies have confirmed the initial results and expanded into other model organisms. The revelation that amyloid-beta is excreted during neuronal activity was huge, because until then we’d assumed that only “diseased” neurons were releasing the toxic protein. This new research showed that not only were healthy neurons releasing amyloid-beta, but they did so every time they were activated.

Sleep: The Good Kind of “Brainwashing”

This brings us back to the question I brought up earlier: how does the brain get rid of all these waste products? If amyloid-beta and other toxic byproducts of neuronal activity were allowed to accumulate unchecked, we’d probably all develop Alzheimer’s disease in infancy. The brain must have some way of cleaning itself. We knew that the waste products eventually ended up being flushed into the cerebrospinal fluid, but no one was sure how exactly it got there from within the brain.

The answer finally came in 2012 with the discovery of the glymphatic system. Researchers found that cerebrospinal fluid was able to enter the brain through a cavity called the subarachnoid space, and flush out toxins via drainage vessels running parallel to the veins. They demonstrated that this pathway was capable of clearing away amyloid-beta from the brain in mice.

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The recently-discovered glymphatic system pumps cerebrospinal fluid through the subarachnoid space into the brain, where it flushes out toxins (including amyloid-beta) through vessels surrounding the veins. Image Source

Only a year later, another breakthrough came. A paper published in Science revealed that the glymphatic system was intricately linked with sleep. During sleep, the channels that carry fluid through your brain expand by 60%, resulting in enhanced glymphatic drainage. The researchers showed that in sleeping mice, the expanded glymphatic vessels cleared away amyloid-beta from the brain twice as quickly as they did when the mice were awake. This paper received a lot of attention because it shed light on a likely function of sleep: to allow the brain to clean itself. New studies quickly came forward with additional evidence, showing that amyloid-beta levels in your brain increase throughout the day and then decrease again when you sleep.

How Sleep Deprivation Can Poison Your Brain

In less than 10 years, our understanding of sleep and Alzheimer’s disease has been turned upside down. We now know that during the day, when neurons are highly active, they release amyloid-beta into the brain fluid. Then when you sleep, your brain’s glymphatic vessels expand and flush away the amyloid-beta and other waste products before they can accumulate to toxic levels. This newly-discovered relationship brings up an ominous possibility: could sleep deprivation reduce amyloid-beta clearance and thus lead to Alzheimer’s disease?

Correlational studies suggest the answer may be yes. Elderly people with insomnia and other sleep disorders are at an increased risk of dementia and have higher levels of amyloid-beta in their brains. A recent study suggested an even more troubling possibility. The paper showed that chronic sleep deprivation may cause neurons to become hyperactive, so that they excrete greater amounts of amyloid-beta into the brain. In turn, this amyloid-beta can interact with other neurons to make it harder to sleep, creating a vicious cycle that could spiral out of control and perhaps lead to Alzheimer’s disease.

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The authors suggested that sleep deprivation could start a vicious cycle, with amyloid-beta deposition increasing exponentially.

The possibility that sleep deprivation could contribute to Alzheimer’s disease is deeply concerning. The CDC reports that 1 in 3 adults routinely do not get at least 7 hours of sleep per night. The problem may be even more severe for elderly people, of whom nearly half report sleep disturbances. By not getting enough sleep, we could be accumulating toxic levels of amyloid-beta in our brains and setting ourselves up for Alzheimer’s disease as we age.

Despite being rather frightening, these recent findings also come with an aspect of hope. While seemingly a major risk factor for Alzheimer’s disease, sleep deprivation is also preventable. By prioritizing sleep as a vital facet of overall health, as well as seeking medical assistance for sleep disorders like insomnia and sleep apnea, we may all be able to reduce our risk for Alzheimer’s and perhaps even other brain diseases. So put down that phone, turn off the lights and head to bed at a reasonable hour tonight. You’ll wake up with a squeaky clean brain in the morning!

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