On your back? Side? Dark side? Mice show how we sleep can trigger or protect our brains from diseases like ALS

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the most common form motor neuron disease. People with ALS gradually lose the ability to initiate and control muscle movement, including the ability to speak, swallow, and breathe.

There is no known cure. But recently, we studied mice and identified a new target in the fight against this devastating disease: the brain’s waste disposal system.

Neurodegenerative diseases – including Parkinson’s disease, Alzheimer’s disease and multiple sclerosis – share many similarities, even though their clinical symptoms and disease progression can look very different. The incidence of these diseases increases with age. They are progressive and relentless and lead to progressive loss of brain tissue. We also see protein waste products building up in the brain.

Our new research looked at how the glymphatic system, which clears waste from the brain, could prevent ALS.



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Protein chains, folds and bad folds

Inside our bodies, long chains of proteins fold into functional shapes that allow them to function specific tasks such as creating antibodies to fight infection, support cells or transport molecules.

Sometimes this process goes wrong, resulting in “misfolded” proteins that clump together to form aggregates. Misfolded proteins can grow and fragment, creating seeds that spread throughout the brain to form new clumps.

The accumulation of protein waste begins early in the neurodegenerative disease process – long before symptoms appear and brain loss occurs. As researchers, we wanted to see if eliminating or slowing the spread of these protein waste products and their seeds could stop or slow the progression of the disease.

Target waste disposal

The glymphatic system removes waste products, including toxic proteins, from the brain.

This cerebral network of fluid-filled spaces, known as Virchow-Robin spaces, is usually turned off when we are awake. But it kicks in during sleep to deliver compounds essential for brain function and to get rid of toxic waste.

This may explain why all creaturesbig and small (even steals), need sleep to survive. (Interestingly, whales and dolphins alternate their sleep between brain hemispheres, keeping the other hemisphere awake to watch for predators and alerting them to breathe!)

Unlike us, dolphins sleep with one side of their brain at a time.
Unsplash/NOAA, CC BY

As we age, the quality of sleep declines and the risk of neurodegenerative disease, including ALS, increases.

Sleep disturbances are also a common symptom of ALS and research has shown that even one night without sleep can lead to increased accumulation of toxic protein waste in the brain. As such, we thought that glymphatic function might be impaired in ALS.



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Aging mice

To study this, we turned to mice. The animals were genetically engineered to express human TDP-43 – the protein implicated in ALS. By feeding these mice food containing an antibiotic (doxycycline), we were able to deactivate the expression of the TDP-43 protein and they aged normally. But when mice are switched to normal food, TDP-43 expression is activated and misfolded proteins begin to accumulate.

Over time, the mice show the classic signs of ALS, including progressive muscle impairments and brain atrophy.

Using magnetic resonance imaging (MRI) to view brain structure, we studied glymphatic function in these mice just three weeks after activating TDP-43 expression.

As we watched the glymphatic system go to work, we saw that TDP-43 mice had worse glymphatic clearance than control mice that had not been genetically modified. It is important to note that these differences were observed very early in the disease process.

Our study provides the first evidence that the glymphatic system could be a potential therapeutic target in the treatment of ALS.

How can we improve lymphatic function?

Not all sleep is equal. Sleep includes both rapid eye movement (REM) sleep and non-REM sleep. This last stage includes slow wave sleep – when the glymphatic system is most active. Sleep therapies that improve this phase may prove particularly beneficial in preventing diseases such as ALS.

Sleeping position is also thought to affect glymphatic clearance.

Research in rodents has demonstrated Glymphatic clearance is more effective in the lateral (or side-lying) position, compared to supine (on your back) or supine (lying on your stomach) positions. The reasons for this are not yet fully understood but may be related to the effects of gravity, compression and tissue stretching.



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Lifestyle choices can also be helpful in improving lymphatic function. Omega 3, found in marine fish, has long been considered beneficial to health and reduces the risk of neurodegenerative diseases. New research shows that these benefits may be partly due to the positive effect of Omega-3 on Glymphatic Function.

Moderate alcohol consumption has been shown to improve waste disposal. In mouse studies, short-term and long-term exposure to small amounts of alcohol have been shown to stimulate glymphatic function while high doses had the opposite effect.

Exercise also proved beneficial.

All of these studies show that small lifestyle changes can improve brain waste disposal to minimize the risk of neurodegenerative disease. Next, research must focus on therapies that directly target the glymphatic system to help those who already suffer from these debilitating conditions.

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