Chronic sleep deprivation linked
to increase in Alzheimer's plaques
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.
Researchers elsewhere had linked mutations in orexin
to narcolepsy, a disorder that is characterized by excessive daytime sleepiness.
The brain has two kinds of receptors for orexin, which is also associated with
regulation of feeding behavior.
When Holtzman's group injected orexin into the brains
of the mice, 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, M.D., Ph.D., a neurology resident and
post-doctoral researcher in Holtzman's lab, performed long-term behavioral experiments
with the mice. She found that three weeks of chronic sleep deprivation accelerated
amyloid plaque deposition in the brain. In contrast, when mice were given almorexant
for two months, plaque deposition significantly decreased, dropping by more than
80 percent 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,"
says Holtzman.
Holtzman notes that not only does the risk of Alzheimer's
increase with age, the sleep/wake cycle also starts to break down, with older
adults progressively getting less and less sleep. Investigators are considering
epidemiological studies of whether chronic sleep loss in young and middle-aged
adults increases risk of Alzheimer's disease later in life.
Holtzman also plans to learn more of the molecular details
of how orexin affects amyloid beta. “We would like to know if there are ways to
alter orexin signaling and its effects on amyloid beta without necessarily modifying
sleep," he says.
Additional studies will address the questions of whether
increased amyloid beta during wakefulness is connected to increased synaptic activity
and whether some aspect of sleep lowers amyloid beta levels independent of synaptic
activity.
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