Chronic sleep deprivation in a mouse model of Alzheimer's disease makes 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, appears to be directly involved in the increase.
Neurodegenerative disorders like Alzheimer's disease and Parkinson's disease often disrupt sleep. The new findings are some of the first indications that sleep loss could play a role in the genesis of such disorders.
"Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer's disease," says senior author David M. Holtzman, M.D., the Andrew and Gretchen Jones Professor and chair of the Department of Neurology at the School of Medicine and neurologist-in-chief at Barnes-Jewish Hospital. "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 uses a technique called in vivo microdialysis to monitor levels of amyloid beta in the brains of mice genetically engineered as a model of Alzheimer's disease. Amyloid beta is a protein fragment that is the principal component of Alzheimer's plaques.
Jae-Eun Kang, Ph.D., a post-doctoral fellow in Holtzman's lab, noticed that brain amyloid beta levels in mice rose and fell in association with sleep and wakefulness, increasing in the night, when mice are mostly awake, and decreasing during the day, when they are mostly asleep.
A separate study of amyloid beta levels in human cerebrospinal fluid led by Randall Bateman, M.D., assistant professor of neurology and a neurologist at Barnes-Jewish Hospital, also showed that amyloid beta levels were generally higher when subjects were awake and lower when they slept.
To confirm the link, Kang learned to use electroencephalography (EEG) on the mice at the Sleep and Circadian Neurobiology Laboratory at Stanford University with researchers Seiji Nishino, M.D., Ph.D., and Nobuhiro Fujiki, M.D., Ph.D. 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, Ph.D., showed that increases in synaptic activity resulted in increased levels of amyloid beta," Holtzman notes. "The brain's synapses may generally be more active when we're awake."
Depriving the mice of sleep caused a 25 percent 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 Holtzman.