Tiny fruit flies offer a few clues to sleep-related Alzheimer’s mysteries
Fruit flies, or rather their tiny brains, can give us some clues about mysteries behind Alzheimer’s disease and how sleep loss plays a role.
A Washington State University researcher is studying the insect’s brain and the effect of sleep patterns, and recently was able to generate physiological characteristics similar to Alzheimer’s in fruit flies.
The results suggest sleep disturbance may be an early warning sign for Alzheimer’s, said Jason Gerstner, an assistant research professor at WSU’s Elson S. Floyd College of Medicine in Spokane. Findings also indicate the brain’s fatty acid binding protein, or FABP, could be key to reducing damaging effects of protein pieces called beta-amyloid that clump together and are associated with plaques forming in brains of Alzheimer’s patients.
One day, further research could lead to discoveries to delay disease onset by using targeted treatments to increase sleep and slow symptoms such as neurodegeneration and memory loss that might be impacted by FABP, Gerstner said.
“A major reason why Alzheimer’s patients are often institutionalized is family and caregivers are no longer able to care for them because they’re up all the time and they have random sleep cycles,” Gerstner said. “As you age, there is also a normal decline in your sleep generally.”
“It seems with this disturbance in sleep, it’s exacerbated in preclinical Alzheimer’s disease. There is an association between sleep disturbance and this plaque formation. We don’t really understand the relationship, but it seems to be bidirectional.”
So it’s a vicious cycle. Or a perfect storm, as Gerstner says.
“Increased sleep disturbance seems to increase more of this beta-amyloid, and in turn this beta-amyloid seems to increase sleep disturbance,” he said.
Alzheimer’s disease is the nation’s sixth leading cause of death, according to the Alzheimer’s Association. It is a type of dementia that causes problems with memory, thinking and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily tasks.
Scientists have known that Alzheimer’s patients commonly experience disturbed sleep. Gerstner’s study, published this past summer in the Journal of Neuroscience Research, looked at the interaction between FABP and beta-amyloid in relation to sleep patterns, examining those dynamics in fruit flies.
“I’m sure people wonder, why fruit flies?” Gerstner said. “When you’re trying to uncover what these molecular mechanisms are that are so fundamental to all animals, one way to do that is to look at a simple organism like the common fruit fly.”
Seventy percent of known disease-causing genes are present in fruit flies, Gerstner added.
The study researched genetically manipulated flies with higher levels of beta-amyloid and compared them to a control group of unmodified flies. Gerstner and co-researchers observed significantly fragmented sleep in the beta-amyloid flies, at an age when they didn’t yet show signs of cognitive decline, the study said.
However, they saw improved sleep in a subgroup of the beta-amyloid flies that had an additional genetic manipulation increasing their FABP levels. The research generated in flies the physiological characteristics of Alzheimer’s by taking beta-amyloid and expressing it in neurons, Gerstner said.
“The accumulation of beta-amyloid, progression of neurodegeneration, cognitive decline and reduced longevity – all those traits are observed in our Alzheimer’s flies, and it looks like fragmented sleep is an early marker,” he said.
“The flies have cognitive impairment, progressive neurodegeneration, and this plaque formation that we’ve found is prior to cognitive dysfunction. When we express this beta-amyloid in neurons, we found their sleep was fragmented, so this seems to mimic or seems to be similar to what we’re now recognizing in the Alzheimer’s disease progression in humans.”
What is known about fruit flies’ sleep patterns and how to measure their sleep? Those are questions co-researcher William Vanderheyden has grown to expect from curious fellow airline passengers when he travels. He has an explanation down pat.
“Sleep has universal features,” Vanderheyden said. “With humans and sleep studies, you attach electrodes. You can’t do that in a fly, but when they’re sleeping, they are laying down, quiescent, not moving. Sleep in a fly is inverse of activity, so when they’re not moving for five minutes, we call that sleep.”
He said fruit flies also provide a powerful genetic tool, because of the ease of manipulating and screening multiple genes. The researchers plan similar studies on other neurological diseases, such as Parkinson’s.
Just as loud noises often wake people, tapping on a test tube filled with the flies jolts them from sleep. The researchers use a recording system with an infrared beam that measures flies’ activity and sleep.
Another tool is an apparatus that takes the tubes, rocks them down and snaps them back up. “We do that all night long,” for various sleep deprivation studies, Vanderheyden said.
In his graduate studies in Wisconsin, Gerstner isolated and cloned FABP from flies, and generated flies that overexpressed FABP. Future research could lead to examining drugs that can influence FABP levels or that protein’s function, he said.
Gerstner hopes a future study can look further into whether FABP will improve cognitive recall. Other researchers have found a scientific method for measuring cognitive decline in flies. It pairs the presence of an odor to a foot shock, and another odor is introduced without shock. Normal fruit flies learn to associate the one smell to adverse stimulus and go to the neutral smell instead.
In earlier research, Gerstner found that genetically manipulated fruit flies with higher FABP levels showed improved sleep and some long-term memory formation. His recent study took that research and paired it with knowledge on beta-amyloid.
Gerstner and co-researchers have studied the insects regarding the genetics of sleep since 1997. He brought that research to WSU Spokane when he took a position here less than three years ago.
“Sleep is exhibited in all animals; we should be able to find in a simple animal what sleep is doing,” he said. “One of the things it’s doing is to help clean out the trash, so to speak.”
One thought is when a person has lots of beta-amyloid pieces binding and becoming aggregate from the day, a certain mechanism occurring during sleep helps offset that, according to Gerstner.
“Sleep is somehow – we’re not sure of the mechanism – helping clear some of these beta-amyloids, we think. We’re in the middle of it. We’re learning.”
Sleep also seems to be important for restoring the ability to have cognitive function, Gerstner added.
Mysteries remain in the scientific world about the impact of plaques occurring from the built-up beta amyloid in the spaces between nerve cells. People can have plaques in the brain but not progress to full-blown Alzheimer’s disease, Gerstner said.
There’s also debate about what role plaques and tangles play as the disease progresses, according to the Alzheimer’s Association. Tangles are twisted fibers of another protein called tau that build up inside cells. Most experts believe they somehow play a role in blocking communication among nerve cells and disrupting processes that cells need to survive, the group says.
The association also describes that the most damaging form of beta-amyloid might be groups of a few pieces rather than the plaques themselves. Small clumps might block cell-to-cell signaling or perhaps activate immune system cells that trigger inflammation and devour disabled cells, the group says.
Although most people develop some plaques and tangles as they age, those with Alzheimer’s tend to develop far more, and in a predictable pattern. It’s the destruction and death of nerve cells that causes memory failure, personality changes and other symptoms, the association says.
More sleep studies could unlock understanding the mechanisms that occur in the brain during slumber. Another universal is the response when people or animals go for long hours without sleep, Gerstner said.
“When you’re out all night, the next day you’re sleeping in making up for sleep lost,” he said. “One of the goals is for us to identify what are the mechanisms, the biological underpinnings, of that need to recover lost sleep.”
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