Drexel University biologist Felice Elefant has discovered a novel way to control sleep disruptions—believed to be an early sign of Alzheimer’s and other neurodegenerative diseases—that could one day lead to new therapies. This research on a unique line of Drosophila—fruit flies—made the recent cover of the journal Genetics.

Memory loss due to normal cognitive decline is a serious, widespread concern as the population ages. Currently, the United States has approximately 38 million people 65 or older. By 2030, that number is projected to soar to 70 million people, many of whom will suffer from neurodegenerative diseases.

“We have to find a way to deal with these cognitive defects,” says Elefant, an associate professor of biology and co-associate head of the Biology Department.

Her research, funded through two National Institutes of Health grants totaling $1.5 million, has helped to advance understanding of the mechanisms at play in the field of epigenetically-regulated genes, particularly those involved in neurodegenerative decline. The relatively new field of epigenetics maintains that the environment around us—whether it’s the food we eat or the stress we experience—can actually change genes and how they behave. Elefant has focused on environmental stimuli that affect the brain’s synaptic plasticity and ultimately its ability to make connections between neurons and thereby retain memories. This is particularly relevant to Huntington’s, Parkinson’s, Alzheimer’s and other neurodegenerative conditions.

Underpinning her research, she says, is the question, “How does experience shape our cognitive ability?”

In earlier work, Elefant’s lab discovered that the protein Tip60, a histone acetyltransferase enzyme, or HAT, regulates how well sleep/wake neurons function, at least in fruit flies. (It likely reflects what happens in us too because fruit flies have a sleep/wake cycle similar to the one in humans, down to the circadian rhythms.)

Tiny chemical markers, responding to the environment, act as writers, readers and erasers on the histone, continuously changing the way the DNA is packaged or wrapped around the histone.

“The environment is impacting what enzymes are being produced and activated,” she says. “Our synaptic activity, our injuries, stresses, environmental stimuli all feed into this enzymatic, epigenetic machinery of writers and erasers.”

This latest research studied whether manipulating the amount of Tip60 in a fruit fly disease model for Alzheimer’s—a model developed at her lab—can fix sleep issues that precede a neurodegenerative diagnosis. Elefant and her students—including former doctoral student Sheila K. Pirooznia, now a post-doc at Johns Hopkins University—collaborated with John E. Zimmerman, a researcher at Center for Sleep and Respiratory Neurobiology at the University of Pennsylvania.

The bottom line? Yes, it can. The notable finding potentially opens the door to new, targeted therapies. In addition to its feature in Genetics, the study will appear in a forthcoming commentary in the journal Fly.

In healthy flies where Tip60 can be manipulated, loss of HAT activity stunted the growth of small ventrolateral neurons, which is harmful to a normal sleep/wake cycle in the fruit flies. At Penn’s Center for Sleep and Respiratory Neurobiology, the flies without Tip60 HAT activity were videotaped round the clock.

“What we found was really remarkable,” Elefant says. “The flies have fragmented night sleep, and sleep too much during the day. That’s just like the subtle, early effects of Alzheimer’s disease in humans.”

Next, Tip60 was manipulated in flies that produced amyloid precursor protein, which leads to the plaques that characterize Alzheimer’s. Once again, taking out Tip60 shortened neurons by suppressing the production of the neuropeptide pigment-dispersing factor, or PDF, in flies. (PDF is equivalent to the neurotransmitter hypocretin in humans.)

But what proved really exciting was that overexpressing Tip60 HAT activity increased PDF in the Alzheimer’s flies and made the neurons grow spectacularly, which in turn ameliorated the sleep/wake problems.

“That shows a neuroprotective role for Tip60 in this disease,” she says, “supporting the concept that if we modulate specific writers, and Tip60 is one of them,

“What we found was really remarkable. The flies have fragmented night sleep, and sleep too much during the day. That’s just like the subtle, early effects of Alzheimer’s disease in humans.”

this could be some kind of therapy.” This is particularly significant because the majority of current epigenetic-based therapies target the erasers—a scattershot approach that can cause harmful side effects.

Next up in her research, says Elefant, is the study of whether these sleep defects are a cause or consequence of memory problems. (In fruit flies, she says, there appears to be a causal effect.) She also wants to better understand the mechanism by which Tip60 works to protect against Alzheimer’s in the disease model and the role of the environment on synaptic plasticity.