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Sleep Found to Clear Toxic Amyloid Beta: Suggests Potential Role for Slowing Alzheimer's Disease

Valeo, Tom

doi: 10.1097/01.NT.0000438829.62018.15
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Two new papers — one in Science, the other in JAMA Neurology — highlight the importance of sound sleep as people age, and hint at new strategies for slowing Alzheimer's disease and other neurological disorders.

Sleep has long been recognized as crucial to cognitive function. Now in an Oct. 18 paper in Science, researchers led by Maiken Nedergaard, MD, of the University of Rochester Medical Center in New York, discovered a key reason why — during sleep the brain doubles the rate at which it removes metabolic debris, including amyloid-beta (Abeta).

At the same time, an Oct. 21 study in Journal of the American Medical Association (JAMA) Neurology reports an inverse relationship between sleep quality and the accumulation of Abeta in the brain.

Together, these two papers highlight the importance of sound sleep as people age, and hint at new strategies for slowing Alzheimer's disease and other neurological disorders.

“I think our paper, in combination with the JAMA Neurology study, suggests that we will have to take sleep problems more seriously,” said Dr. Nedergaard, co-director of the university's Center for Translational Neuromedicine. “We need more data, but common sense tells you that these findings demonstrate the importance of good sleep to brain health.”

The plumbing system of the brain, which Dr. Nedergaard has dubbed the “glymphatic system,” solves a mystery that has long puzzled brain researchers — how does the brain get rid of metabolic byproducts without the help of the lymphatic system, which performs that job in the rest of the body?

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In previous work, Dr. Nedergaard and her colleagues used in vivo two-photon imaging and other techniques to follow the flow of tracer molecules through the interstitial space of the mouse brain, revealing the presence of a clearance system unique to the brain.

In a 2012 paper in Science Translational Medicine, they described how they injected tracer molecules into the subarachnoid CSF of mice, and found that the tracer rapidly entered the brain, flowing through a tiny space located between the outer wall of small arteries and a barrier created by astrocytic endfeet. The tracer then flowed out of the brain through similar channels along veins, eventually reaching the ventricles. Fluorescent-tagged Abeta peptide was removed along this route, suggesting that impaired clearance could lead to the type of accumulation believed to impair synaptic function and thereby contribute to Alzheimer's disease and other forms of neurodegeneration.

Then, in the March 2013 issue of The Journal of Clinical Investigation, Dr. Nedergaard and her team provided proof of concept that dynamic contrast-enhanced MRI could analyze glymphatic function in a way that “may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain,” according to the authors.

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In the Science paper, the researchers gleaned more details about the glymphatic system by injecting fluorescent tracers into the CSF of mice and using in vivo two-photon imaging to peer into the brain and watch the dye flow when the mice were awake, anesthetized, and sleeping. They found that the mice cleared Abeta injected into the brain twice as fast while they were sleeping or anesthetized as when awake. An inert tracer also was cleared twice as fast when the mice were not awake. The interstitial space volume increased by more than 60 percent when the mice were asleep, allowing greater glymphatic flow.

“Because biological activity is inevitably linked to the production of metabolic degradation products, it is possible that sleep subserves the important function of clearing multiple potentially toxic CNS waste products,” the authors concluded. “[T]he restorative function of sleep may be due to the switching of the brain into a functional state that facilitates the clearance of degradation products of neural activity that accumulate during wakefulness.”

The study was funded by the NIH National Institute of Neurological Disorders and Stroke.

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The JAMA Neurology paper used data from 70 adults enrolled in the Baltimore Longitudinal Study of Aging to link shorter self-reported sleep duration and poorer sleep quality to the accumulation in the brain of Abeta. However, the data did not allow the researchers to infer whether shorter sleep duration and poorer sleep quality were causes or effects of amyloid deposition, according to lead author Adam Spira, PhD, assistant professor in the department of mental health at the Johns Hopkins Bloomberg School of Public Health.

“I think in all likelihood it's both,” Dr. Spira said. “Sleep disturbances may begin a cascade that contributes to Alzheimer's disease, but once the brain pathology accumulates, research suggests that the pathology itself may cause changes in the quality of sleep. A decline in sleep quality may begin this process, but once amyloid deposition reaches a certain level, that may cause further changes in sleep.”

Dr. Spira considers the findings of Dr. Nedergaard's group strong support for the findings of his own group. “The mechanism they have elucidated caught me by surprise, but it could help account for the findings we observed,” he said. “I think it's terrific that these findings were published at the same time. Given the epidemic [of Alzheimer's] we're facing, I think these results should encourage neurologists to take sleep disorders seriously, and not dismiss them as part of aging.”

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Although sleep disorders are known to contribute to cognitive problems, depression, and other disorders, the conclusion that sleep promotes the removal of toxins from the brain “goes a little beyond the data” in the Science paper, according to Mark Mattson, PhD, chief of the Laboratory of Neurosciences at the National Institute on Aging Intramural Research Program, and a professor of neuroscience at Johns Hopkins University.

“They did not even consider that this increase in interstitial volume, which they suggest increases the movement of chemicals and proteins out of the brain, would also likely remove good things, like neurotrophic factors,” said Dr. Mattson. “There's a lot of evidence that production of neurotrophic factors is good for the brain, critical for learning and memory, and that impaired neurotrophic signaling may contribute to Alzheimer's disease.”

However, recent work by researchers at Washington University in St. Louis anticipated the findings of Dr. Nedergaard's team, including the observations that Abeta levels decline during sleep. In a 2009 paper in Science, for example, they reported that the amount of Abeta found in the interstitial fluid of a mouse model of Alzheimer's disease increased markedly during periods of sleep deprivation.

Then, in a 2011 paper in the Archives of Neurology, they reported that Abeta in the spinal fluid of humans rose during waking hours and fell during sleep — a pattern found to be most pronounced in healthy young people.

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“We certainly thought some mechanism of sleep modulated Abeta production, but we didn't anticipate that sleep would increase the flow of interstitial fluid, which is what the (Science) paper shows very convincingly,” said Randall J. Bateman, MD, Knight Distinguished professor of neurology at the Washington University School of Medicine, who has done research on the sleep-wake cycle and fluctuation of Abeta in mice with Alzheimer's disease pathology. “I just about hit the floor when I saw the paper [by Dr. Nedergaard and colleagues]. The magnitude of the effect they found is quite impressive. If we had drugs that improved clearance that well, they'd be remarkable.”

Now Dr. Bateman would like to see the findings of Dr. Nedergaard's group validated in other animal models and in humans. “If the increase in amyloid-beta clearance during sleep happens in humans, does lack of sleep lead to more Alzheimer's disease?” he said. “What may impair the clearance mechanism? Diabetes? High blood pressure? Age? Can we figure out a way to enhance this sleep clearance mechanism to lower the risk of Alzheimer's and other diseases?”

The discovery of the clearance mechanism is certain to “open the floodgates” to new research, Dr. Bateman believes. “The mechanism is just so beautiful,” he said. “It's characteristic of nature to work out an extremely elegant, simple solution and solve lots of problems with it. I never would have predicted that sleep would increase the interstitial space and clearance so much.”

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•. Spira AP, Gamaldo AA, An Y, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol 2013 ; E-pub 2013 Oct. 21.
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© 2013 American Academy of Neurology