Chronic sleep deprivation makes Alzheimer’s brain plaques appear earlier and more often in a mouse model of Alzheimer’s disease, according to researchers at Washington University School of Medicine in St Louis. The researchers also found that orexin, a protein that helps regulate the sleep cycle, appears to be directly involved in the increase. 

The new findings, reported in Science Express, are some of the first indications that sleep loss could play a role in the genesis of neurodegenerative disorders like Alzheimer’s.

Depriving the mice of sleep caused a 25% increase in amyloid beta levels. Levels were lower when mice were allowed to sleep. Blocking a hormone previously linked to stress and amyloid beta production had no effect on these changes, suggesting that they weren’t caused by the stress of sleep deprivation, according to senior author David M. Holtzman, MD, chair of the Department of Neurology at the School of Medicine.

"Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer’s disease," said Holtzman. "The results also suggest that we may need to prioritize treating sleep disorders not only for their many acute effects but also for potential long-term impacts on brain health."

Holtzman’s laboratory used a technique called in vivo microdialysis to monitor levels of amyloid beta (a protein fragment that is the principal component of Alzheimer’s plaques) in the brains of mouse models of Alzheimer’s disease. Two separate studies in the lab showed that amyloid beta levels were generally higher when subjects were awake and lower when they slept.

To confirm the link, the researchers used electroencephalography (EEG) on the mice at the Sleep and Circadian Neurobiology Laboratory at Stanford University. The EEG readings let researchers more definitively determine when mice were asleep or awake and validated the connection: Mice that stayed awake longer had higher amyloid beta levels.

"This makes sense in light of an earlier study in our lab where John Cirrito, PhD, showed that increases in synaptic activity resulted in increased levels of amyloid beta," said Holtzman. "The brain’s synapses may generally be more active when we’re awake."

Working on previous research of other labs that linked mutations in orexin to narcolepsy, Holtzman’s group injected orexin into the brains of the mice. When injected, the mice stayed awake longer and amyloid beta levels increased. When researchers used a drug called almorexant to block both orexin receptors, amyloid beta levels were significantly lower and animals were awake less.

Miranda M. Lim, MD, PhD, a neurology resident and postdoctoral researcher in Holtzman’s lab, performed long-term behavioral experiments with the mice. Lim found that 3 weeks of chronic sleep deprivation accelerated amyloid plaque deposition in the brain. However, when mice were given almorexant for 2 months, plaque deposition significantly decreased, dropping by more than 80% in some brain regions.

"This suggests the possibility that a treatment like this could be tested to see if it could delay the onset of Alzheimer’s disease," said Holtzman. "We would like to know if there are ways to alter orexin signaling and its effects on amyloid beta without necessarily modifying sleep."

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