Targeting Sleep-Wake Protein May Prevent Alzheimer's

A new study reported in The Journal of Experimental Medicine suggests an approach to preventing Alzheimer's disease may lie in targeting orexin.

Researchers from the School of Medicine at Washington University in St. Louis (WUSTL) came to this conclusion after they found eliminating orexin in mice made them sleep longer and significantly slowed the production of brain plaques.

Brain plaques are abnormal clusters of amyloid beta protein fragments that build up between nerve cells and a known hallmark of Alzheimer's disease. Scientists believe that slowing or stopping this build up could slow or stop the disease.

Orexin is a protein that stimulated wakefulness. It is produced by cells located in the hypothalamus - a small section of the brain that controls many functions, including sleep.

Low levels of orexin are linked to narcolepsy, a condition marked by excessive sleepiness and frequent periods of daytime sleeping.

Blocking orexin to increase sleep may be a way to reduce risk of Alzheimer's

In previous studies, WUSTL researchers have shown that in both people and mice, sleep loss contributes to the production of brain plaques and increases the risk of developing dementia.

Professor David M. Holtzman, senior author of the new study and head of the Department of Neurology at WUSTL School of Medicine, says the new study shows "we should be looking hard at orexin as a potential target for preventing Alzheimer's disease," and:

"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 further."

Mice lacking orexin slept longer and developed only half as many brain plaques

For the new study, the team used mice that had been genetically engineered to develop brain plaques. But when they bred these same mice lacking the gene for orexin, their offspring slept longer and only developed half the number of plaques as mice that could still produce orexin.

Prof. Holtzman says the hypothalamus cells that produce orexin "have branches that carry orexin throughout the brain, and the protein acts like a switch. If you stimulate orexin production in sleeping mice, they wake up immediately."

The team found that the mice with no orexin typically slept an extra hour or more during the 12-hour period when mice with orexin were more active.

When they repeated the experiment the other way around and artificially increased orexin levels throughout the brain, the researchers found the mice were awake for longer periods and developed more brain plaques.

Orexin 'only affects plaque levels when it also affects sleep'

But when the team altered orexin levels in only part of mice's brain - not throughout the brain - this did not alter the amount of time the animals slept for and neither did it change plaque levels.

This last experiment shows orexin only affects plaque levels when it also affects sleep, says Prof. Holtzman, which means "we will have to think carefully about how to target it for Alzheimer's prevention. 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."

The team is now looking at how sleep medication might affect the production of amyloid beta and the accumulation of plaques. They hope to assess drugs like the recently FDA-approved Belsomra - the first to target orexin.

In October 2014, Medical News Today learned of a study that found diets enriched with walnuts slow Alzheimer's progression in mice. The finding follows previous research that found an extract in walnuts may protect against oxidative stress caused by beta amyloid protein.