Researchers Link Alzheimer's to a Lack of Sleep

Losing sleep could lead to losing brain cells, a new study suggests. Levels of a protein that forms the hallmark plaques of Alzheimer's disease rise in the brains of mice and in the spinal fluid of people during wakefulness and fall during sleep, researchers report online September 24 in Science. Mice that didn't get enough sleep for three weeks also had more plaques in their brains than well-rested mice, the team found.

Scientists knew that having Alzheimer's disease was associated with poor sleep, but they had thought that Alzheimer's disease caused the sleep disruption.

"This is the first experimental study that clearly shows that disrupted sleep may contribute to the disease process," says Peter Meerlo, a neuroscientist at the University of Groningen in the Netherlands. "It shows that chronic sleep loss, in the long run, changes the brain in ways that may contribute to disease." A vicious cycle could result if sleep loss leads to Alzheimer's disease and the disease leads to more sleep loss, he says.

Researchers led by David Holtzman of Washington University in St. Louis used a method called microdialysis to measure the levels of amyloid-beta protein in the fluid between brain cells of mice. Amyloid-beta sometimes twists into a sticky form and clumps together, forming plaques. Scientists don't yet understand how, but they think that amyloid-beta clumping eventually leads to the death of neurons and to Alzheimer's disease symptoms (SN: 8/16/08, p. 20).

Although levels of amyloid-beta in the brain tissue of the mice didn't seem to change, Holtzman's group found that levels of the protein released into brain fluid did rise and fall throughout the day. "We didn't know it would coordinate with sleep and wakefulness," Holtzman says. Levels of the protein in the brain fluid increased in mice during the night -- when mice are mostly awake -- and fell during the day when mice sleep. The longer the mice stayed awake, the more amyloidbeta levels increased, the team found. The team also measured amyloid-beta levels in the cerebral spinal fluid of some healthy young people and found the same pattern as in the mice. Amyloid- beta levels increase when people are awake and fall during sleep. Giving mice a shot of a hormone called orexin, which promotes wakefulness, also caused amyloid-beta levels to increase. And blocking orexin's activity led to a decrease in the amount of protein released into brain fluid. The researchers don't yet know if orexin is directly responsible for helping release amyloidbeta into brain fluid or if by keeping animals awake, orexin allows more time for levels of the protein to build up. Holtzman's team also studied mice genetically predisposed to build Alzheimer's plaques. For three weeks, the team allowed some of the animals to sleep only four hours a. day while others slept normally. Sleep-deprived mice made more plaques than well-rested mice. A drug that blocks orexin's action stopped plaque buildup in well-rested, mutant mice, the researchers discovered.
Studies in people haven't shown a link between Alzheimer's disease and chronic sleep loss, but Holtzman speculates that lack of sleep, particularly in midlife, could hasten onset of the disease in genetically susceptible individuals. "Mechanistically we don't understand why [sleep] is manipulating amyloid-beta rhythms," says Sangram Sisodia of the University of Chicago, "but we do know it's doing something good for the brain.... There's a clear message here about why it is so important to sleep."
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