New Alzheimer’s Disease Fighter may be Protein that
Eliminating protein called orexin made mice sleep
longer and strongly slowed the production of brain plaques
24, 2014 - Scientists at Washington University, who earlier established
links between sleep problems and Alzheimer's, now say a protein that
stimulates the brain to awaken from sleep may be a target for preventing
The researchers at WU School of Medicine in St.
Louis have shown in people and in mice that sleep loss contributes to
the growth of brain plaques characteristic of Alzheimer's, and increases
the risk of dementia.
The new research, in mice, demonstrates that
eliminating that protein - called orexin - made mice sleep for longer
periods of time and strongly slowed the production of brain plaques.
"This indicates we should be looking hard at orexin
as a potential target for preventing Alzheimer's disease," said senior
author David M. Holtzman, MD, head of the Department of Neurology.
"Blocking orexin to increase sleep in patients with sleep abnormalities,
or perhaps even to improve sleep efficiency in healthy people, may be a
way to reduce the risk of Alzheimer's. This is important to explore
The research appears Nov. 24 in The Journal
of Experimental Medicine.
Brain plaques, which are mostly made of a protein
called amyloid beta, accumulate in the brain before the onset of
Alzheimer's symptoms such as memory loss, personality changes and
disorientation. These plaques continue to collect as the disease
progresses. Scientists think that slowing or stopping this buildup could
slow or stop the disease.
In the current study, the researchers worked with
mice genetically engineered to develop a buildup of amyloid in the
brain, which is characteristic of Alzheimer's disease. When the
researchers bred these mice with mice lacking the gene for orexin, their
offspring slept longer and developed only half as many Alzheimer's
plaques, compared with the mice that had the orexin protein.
Orexin is made by cells in the brain's hypothalamus
that stimulate wakefulness.
"These cells have branches that carry orexin
throughout the brain, and the protein acts like a switch," said Holtzman,
the Andrew B. and Gretchen P. Jones Professor of Neurology. "If you
stimulate orexin production in sleeping mice, they wake up immediately."
Low orexin levels are associated with narcolepsy, a
condition marked by excessive sleepiness and frequent daytime sleeping
spells. The mice with no orexin typically slept an extra hour or more
during the 12-hour period when mice with orexin became more active.
When scientists reversed the experiment and
artificially increased orexin levels throughout the brain, the mice
stayed awake longer and developed more Alzheimer's-like plaques.
But if the researchers changed orexin levels only
in part of the brain - a change that did not affect the amount of time
mice slept - plaque levels were unaffected.
"The fact that orexin can only affect plaques when
it also affects sleep means we will have to think carefully about how to
target it for Alzheimer's prevention," Holtzman said. "But the declines
in plaque levels that we saw in the mice were very strong, so we're
still very interested in exploring its potential for reducing risk."
He and his colleagues, including first author Jee
Hoon Roh, MD, PhD, currently are studying the effects of sleep
medications on amyloid beta production and plaque accumulation. The FDA
recently approved Belsomra, the first sleep medication that affects
orexin, and the researchers hope to assess it or similar drugs in the
This work was supported by the American Academy of
Neurology Clinical Research Training Fellowship; the Basic Science
Research Program through the National Research Foundation of Korea (NRF)
funded by the Ministry of Science, ICT and Future Planning (MSIP),
2013R1A1A1012925; an NRF MRC grant funded by the Korean government (MSIP),
2008-0062286; the Korea Institute of Science and Technology
Institutional Program, 2E24242-13-110; grants 2014-0783, 2014-7203 and
2014-9077 from the Asan Institute for Life Sciences; an Ellison Medical
Foundation Senior Scholar Award; the National Institutes of Health (NIH),
P01NS074969, R01NS090934 and P30NS057105; the JPB Foundation; and the
Cure Alzheimer's Fund.
Washington University School of Medicine's 2,100
employed and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals.
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