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Lack of Sleep Linked to Alzheimer’s Plaques in Mice

People with Alzheimer's and other neurodegenerative diseases often have trouble sleeping. Now a new study suggests that sleep problems may actually contribute to the disease process. Researchers report that disrupted sleep can lead to the buildup of brain plaques—a hallmark of Alzheimer's disease—in mice.

Alzheimer's disease is the most common cause of dementia among older people. It's marked by dense protein clumps, called amyloid plaques, that form between brain cells. The plaques are made mostly of a protein fragment called amyloid-beta, produced by nerve cells and released into the surrounding brain fluid.

The many factors that lead to the formation of amyloid plaques are poorly understood. To gain a better understanding of amyloid-beta in the brain, a research team led by Dr. David M. Holtzman of the Washington University in St. Louis used a technique called microdialysis to monitor levels in living mouse brains. Their work was funded in part by NIH's National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Mental Health (NIMH).

As reported in the online edition of Science on September 24, 2009, the researchers found that amyloid-beta levels fluctuate each day, rising during active periods and falling while at rest. The longer mice stayed awake, the greater the increase in amyloid-beta levels in the fluid that surrounds brain cells. Tests confirmed that the fluctuations were not significantly affected by light exposure, time of day or a stress hormone.

To see if humans have similar fluctuations, the researchers measured amyloid-beta levels over a 33 hour period in the cerebrospinal fluid of 10 healthy male volunteers. They found that amyloid-beta levels fluctuate in humans with the time of day, too.

To investigate the molecular mechanisms that underlie amyloid-beta fluctuations, the researchers turned their attention to orexin, a hormone associated with the sleep-wake cycle. Orexin promotes wakefulness. Its malfunction has been linked to narcolepsy, a disorder marked by excessive daytime sleepiness.

Giving mice infusions of orexin caused the mice to stay awake longer and their amyloid-beta levels to rise. Blocking orexin's activity both lowered amyloid-beta levels and prevented normal amyloid-beta fluctuations.

To test whether chronic sleep deprivation could promote plaque formation, the scientists studied mice that are known to be predisposed to develop Alzheimer's-like plaques. After 3 weeks, mice allowed to sleep only 4 hours a day had markedly greater deposition of amyloid plaques than well-rested mice. Daily doses of a drug that blocks orexin activity helped prevent the buildup of plaque; after 2 months, plaque deposition dropped by more than 80% in some brain regions.

“Orexin or compounds it interacts with may become new drug targets for treatment of Alzheimer's disease,” says Holtzman. Still, the mouse studies are preliminary, and additional research will be needed to clarify if lack of sleep and orexin truly play a role in the development of amyloid plaques in humans.

—by Vicki Contie