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Sleep loss linked to increase in Alzheimer’s plaques

Submitted by on 14 July, 2022 – 4:32 pm
Chronic sleep deprivation in a murine model of Alzheimer’s disease causes Alzheimer’s brain plaques appear earlier and more often, researchers at Washington University School of Medicine in St. Louis report online this week in Science Express.

They also found that orexin, a protein that helps regulate the sleep cycle seems to be directly involved in the increase.

Neurodegenerative diseases like Alzheimer’s and Parkinson’s disease often disrupt sleep. The new findings are some early indications that sleep loss may play a role in the genesis of these disorders.

“Orexin or compounds that interact with can become new drug targets for treating Alzheimer’s disease,” says lead author David M. Holtzman, MD, the Andrew and Gretchen Jones Professor and Head, Department of Neurology, Faculty of Medicine and neurologist-in-chief at Barnes-Jewish Hospital. “The results also suggest that we may need to prioritize the treatment of sleep disorders, not only for his many acute effects, but also for potential long-term effects on brain health.”

Holtzman Laboratory uses a technique called in vivo microdialysis to monitor the levels of beta-amyloid in the brain of genetically modified mice as a model of Alzheimer’s disease. Beta amyloid is a protein fragment that is the main component of Alzheimer’s plaques.

Jae-Eun Kang, Ph.D., a postdoc in the Holtzman lab, realized that the brain levels of beta-amyloid in mice up and down in association with sleep and wakefulness, increased night, when mice are mostly awake, and decreased during the day, when they are mostly sleeping.

An independent study of the levels of beta-amyloid in human cerebrospinal fluid directed by Randall Bateman, MD, assistant professor of neurology and neurologist at Barnes-Jewish Hospital, also showed that beta-amyloid levels were generally higher when subjects were lower when awake and asleep.

To confirm the link, Kang learned to use an electroencephalogram (EEG) in mice in sleep and circadian Laboratory of Neurobiology at Stanford University researchers Seiji Nishino, MD, Ph.D., and Nobuhiro Fujiki, MD, Ph . D. EEG readings allow researchers to determine more definitively when the mice were asleep or awake and validate the connection: The mice stayed awake longer had higher levels of beta-amyloid.

“This makes sense in light of a previous study in our laboratory, where John cirrita, Ph.D., showed that increases in synaptic activity result in higher levels of beta amyloid,” says Holtzman. “Synapses in the brain in general, may be more active when awake.”

To deprive mice of sleep caused a 25 percent increase in the levels of amyloid beta. The levels were lower when mice were allowed to sleep. Blocking a hormone previously associated with stress and beta-amyloid production had no effect on these changes, suggesting that they were not caused by the stress of sleep deprivation, according to Holtzman.

Researchers elsewhere have linked mutations in orexin in narcolepsy, a disorder characterized by excessive daytime sleepiness. The brain has two types of orexin receptors, which also is associated with regulation of feeding behavior.

When the group of Holtzman orexin injected into the brains of mice, the mice stayed awake longer, and increased levels of beta-amyloid. When the researchers used a drug called almorexant block the orexin receptors, the beta-amyloid levels were significantly lower and the animals were awake less.

Miranda M. Lim, MD, Ph.D., a neurology resident and post-doctoral researcher in Holtzman’s lab, conducted experiments in the long term behavior of mice. She found that three weeks of chronic sleep deprivation accelerated the deposition of amyloid plaques in the brain. In contrast, when mice received almorexant for two months, the deposit of plaque was significantly reduced from more than 80 percent in some brain regions.

“This suggests the possibility that a treatment like this could be a test to see if it could delay the onset of Alzheimer’s disease,” says Holtzman.

Holtzman notes that not only increase the risk of Alzheimer’s disease with age, sleep / wake cycle also begins to break down, with progressively older adults sleep less and less. Researchers are studying the epidemiological studies that chronic sleep loss in young and middle-aged adults increases the risk of Alzheimer’s disease later in life.

Holtzman also plans to learn more about the molecular details of how orexin affects beta-amyloid.

“We wonder whether there are ways to alter orexin signaling and its effects on beta-amyloid without changing the dream,” he says.

Further studies will address whether beta amyloid increased during wakefulness is connected to increased synaptic activity and whether any aspect of sleep lowers levels of amyloid beta independent of synaptic activity.

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