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Sleep Loss Encourages Spread of Toxic Alzheimer’s Protein

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Credit: iStock/bowdenimages

In addition to memory loss and confusion, many people with Alzheimer’s disease have trouble sleeping. Now an NIH-funded team of researchers has evidence that the reverse is also true: a chronic lack of sleep may worsen the disease and its associated memory loss.

The new findings center on a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease. In the healthy brain, active neurons naturally release some tau during waking hours, but it normally gets cleared away during sleep. Essentially, your brain has a system for taking the garbage out while you’re off in dreamland.

The latest findings in studies of mice and people further suggest that sleep deprivation upsets this balance, allowing more tau to be released, accumulate, and spread in toxic tangles within brain areas important for memory. While more study is needed, the findings suggest that regular and substantial sleep may play an unexpectedly important role in helping to delay or slow down Alzheimer’s disease.

It’s long been recognized that Alzheimer’s disease is associated with the gradual accumulation of beta-amyloid peptides and tau proteins, which form plaques and tangles that are considered hallmarks of the disease. It has only more recently become clear that, while beta-amyloid is an early sign of the disease, tau deposits track more closely with disease progression and a person’s cognitive decline.

Such findings have raised hopes among researchers including David Holtzman, Washington University School of Medicine, St. Louis, that tau-targeting treatments might slow this devastating disease. Though much of the hope has focused on developing the right drugs, some has also focused on sleep and its nightly ability to reset the brain’s metabolic harmony.

In the new study published in Science, Holtzman’s team set out to explore whether tau levels in the brain naturally are tied to the sleep-wake cycle [1]. Earlier studies had shown that tau is released in small amounts by active neurons. But when neurons are chronically activated, more tau gets released. So, do tau levels rise when we’re awake and fall during slumber?

The Holtzman team found that they do. The researchers measured tau levels in brain fluid collected from mice during their normal waking and sleeping hours. (Since mice are nocturnal, they sleep primarily during the day.) The researchers found that tau levels in brain fluid nearly double when the animals are awake. They also found that sleep deprivation caused tau levels in brain fluid to double yet again.

These findings were especially interesting because Holtzman’s team had already made a related finding in people. The team found that healthy adults forced to pull an all-nighter had a 30 percent increase on average in levels of unhealthy beta-amyloid in their cerebrospinal fluid (CSF).

The researchers went back and reanalyzed those same human samples for tau. Sure enough, the tau levels were elevated on average by about 50 percent.

Once tau begins to accumulate in brain tissue, the protein can spread from one brain area to the next along neural connections. So, Holtzman’s team wondered whether a lack of sleep over longer periods also might encourage tau to spread.

To find out, mice engineered to produce human tau fibrils in their brains were made to stay up longer than usual and get less quality sleep over several weeks. Those studies showed that, while less sleep didn’t change the original deposition of tau in the brain, it did lead to a significant increase in tau’s spread. Intriguingly, tau tangles in the animals appeared in the same brain areas affected in people with Alzheimer’s disease.

Another report by Holtzman’s team appearing early last month in Science Translational Medicine found yet another link between tau and poor sleep. That study showed that older people who had more tau tangles in their brains by PET scanning had less slow-wave, deep sleep [2].

Together, these new findings suggest that Alzheimer’s disease and sleep loss are even more intimately intertwined than had been realized. The findings suggest that good sleep habits and/or treatments designed to encourage plenty of high quality Zzzz’s might play an important role in slowing Alzheimer’s disease. On the other hand, poor sleep also might worsen the condition and serve as an early warning sign of Alzheimer’s.

For now, the findings come as an important reminder that all of us should do our best to get a good night’s rest on a regular basis. Sleep deprivation really isn’t a good way to deal with overly busy lives (I’m talking to myself here). It isn’t yet clear if better sleep habits will prevent or delay Alzheimer’s disease, but it surely can’t hurt.

References:

[1] The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. Science. 2019 Jan 24.

[2] Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TLS, Holtzman DM. Sci Transl Med. 2019 Jan 9;11(474).

Links:

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)

Holtzman Lab (Washington University School of Medicine, St. Louis)

NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering


Poor Sleep Habits in Adolescence Correlated with Cardiovascular Risk

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Stressed by schoolwork

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Just ask any parent or teacher, most of today’s teens and pre-teens don’t seem to get enough sleep. And what sleep they do get is often poor quality—no great surprise, given that smartphones and other electronic devices are usually never far from their reach. Now, an NIH-funded team has uncovered the strongest evidence yet that this lack of quality sleep may be setting our kids up for some serious health issues later in life.

The team’s study of more than 800 adolescents, ages 11 through 13, confirmed that many are getting an insufficient amount of undisturbed, restful sleep each night. While earlier studies had found a link between sleep duration and obesity [1], the new work shows that a wide range of other cardiovascular risk factors are affected by both too little sleep and poor sleep quality [2]. When compared to well-rested kids, sleep-deprived youth were found to have higher blood pressure, bigger waistlines, and lower levels of high density lipoprotein (HDL) cholesterol, which is associated with lower risk of cardiovascular disease.


Creative Minds: Does Human Immunity Change with the Seasons?

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Micaela Martinez

Micaela Martinez

It’s an inescapable conclusion from the book of Ecclesiastes that’s become part of popular culture thanks to folk legends Pete Seeger and The Byrds: “To everything (turn, turn, turn), there is a season.” That’s certainly true of viral outbreaks, from the flu-causing influenza virus peaking each year in the winter to polio outbreaks often rising in the summer. What fascinates Micaela Martinez is, while those seasonal patterns of infection have been recognized for decades, nobody really knows why they occur.

Martinez, an infectious disease ecologist at Princeton University, Princeton, NJ, thinks colder weather conditions and the tendency for humans to stay together indoors in winter surely play a role. But she also thinks an important part of the answer might be found in a place most hadn’t thought to look: seasonal changes in the human immune system. Martinez recently received an NIH Director’s 2016 Early Independence Award to explore fluctuations in the body’s biological rhythms over the course of the year and their potential influence on our health.


How Sleep Resets the Brain

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dendrites

Caption: Colorized 3D reconstruction of dendrites. Neurons receive input from other neurons through synapses, most of which are located along the dendrites on tiny projections called spines.
Credit: The Center for Sleep and Consciousness, University of Wisconsin-Madison School of Medicine

People spend about a third of their lives asleep. When we get too little shut-eye, it takes a toll on attention, learning and memory, not to mention our physical health. Virtually all animals with complex brains seem to have this same need for sleep. But exactly what is it about sleep that’s so essential?

Two NIH-funded studies in mice now offer a possible answer. The two research teams used entirely different approaches to reach the same conclusion: the brain’s neural connections grow stronger during waking hours, but scale back during snooze time. This sleep-related phenomenon apparently keeps neural circuits from overloading, ensuring that mice (and, quite likely humans) awaken with brains that are refreshed and ready to tackle new challenges.


Explaining the Traveler’s First-Night Sleep Problem

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Sleepy in the morning

Stock photo/Wavebreakmedia Ltd

This past weekend, I attended a scientific meeting in New York. As often seems to happen to me in a hotel, I tossed and turned and woke up feeling not very rested. The second night I did a bit better. Why is this? Using advanced neuroimaging techniques to study volunteers in a sleep lab, NIH-funded researchers have come up with a biological explanation for this phenomenon, known as “the first-night effect.”

As it turns out, the first night when a person goes to sleep in a new place, a portion of the left hemisphere of his or her brain remains unusually active, apparently to stay alert for any signs of danger. The new findings not only provide important insights into the function of the human brain, they also suggest methods to prevent the first-night effect and thereby help travelers like me in our ongoing quest to get a good night’s sleep.


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