Sleep Disorders as Prologue to Disease: From the Archives

What a (incremental) difference seven years make. In 2009, when we wrote about Dana Alliance member David Holtzman’s work, the headline was “Could Sleep Disorders Contribute to Alzheimer’s?” This month, Scientific American describes the work he and colleagues at Washington University School of Medicine in St. Louis are doing using the headline “Why Sleep Disorders May Precede Parkinson’s and Alzheimer’s.” We’ve gone from “maybe take a look” to “what’s the mechanism” on evidence for a link between sleep troubles and risk for neurodegenerative disorders has come.

Scientific American’s Simon Makin calls the Holtzman lab’s 2009 discovery the “best evidence for a causal relationship” From our story:

Beta-amyloid is produced by neurons even in healthy people, but the body quickly eliminates it. Why it tends to clump and persist in Alzheimer’s remains the subject of wide-ranging research. David Holtzman and colleagues from Washington University in St. Louis, Missouri, for instance, started their experiment by measuring beta-amyloid levels in mice genetically modified to develop Alzheimer’s-like symptoms.

But they found something unexpected: the levels of the amyloid protein appeared to fluctuate daily.

“To see that over the course of a day it could change by as much as 50 percent, even 100 percent, every single day, was striking,” Holtzman says. “Once we saw that, then we really wanted to understand why.”

To find out what was causing the daily fluctuations, Holztman and his colleagues measured beta-amyloid levels while monitoring the sleep-wake cycles of the mice. They discovered that levels were higher during wakefulness than during sleep. Changing the light conditions did not affect the daily variations, indicating that it was not light exposure that was controlling the changes in beta-amyloid levels, but the sleep-wake cycle itself.

The researchers then measured the levels when the mice were forced to stay awake. Levels of the protein were significantly higher during sleep deprivation. In addition, animals that were sleep deprived for three weeks showed greater amyloid plaque formation than mice with normal sleep-wake cycles.

Since then, the team has genetically engineered mice to have faulty circadian clocks, which control sleep-wake cycles. From the Scientific American story:

The mice gradually developed signs of pathology, including loss of synapses (the connection points among neurons), free radical damage and signs of inflammation. “The mouse gets a kind of neuroinflammatory syndrome that’s pretty striking,” [Erik] Musiek [also of Washington University] says. “Circadian clock genes clearly play some important role in maintaining the brain.”

The team also saw reduced activity of genes that defend against free radicals, suggesting lack of this protection was a major cause of damage, according to the study, which was published in 2013. Processes like free radical damage, inflammation and others have all been implicated in neurodegeneration. They can also influence, and be influenced by, the circadian clock, providing potential paths by which circadian disturbances and neurodegeneration could affect each other. “Sorting out the mechanisms of this is probably the most important next step in this field,” Holtzman says.

Nothing they or other researchers have found so far suggests that circadian factors are the cause of neurodegeneration. They might be risk factors, though, that we could modify, theoretically preventing or holding off disease.  “If we could lower that risk and stave off disease by a few years, millions fewer people every year would be affected,” Musiek told the magazine.

Holtzman and Musiek also wrote a review of the scientific literature in this area in November for Science magazine (behind a paywall).

– Nicky Penttila

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