Researchers from Drexel University reversed symptoms of Alzheimer’s disease in fruit flies by restoring the balance between two epigenetic enzymes that regulate gene expression.
Early in the progression of Alzheimer’s disease, cognitive impairment, such as difficulties with learning and memory, may be tied to the presence of elevated levels of the enzyme HDAC2. HDAC2 helps control how genes linked to learning and memory are expressed. When HDAC2 overwhelms the enzyme it is paired with, called Tip60 HAT, it appears that it represses genes and leads to problems with neuroplasticity — the brain’s ability to adapt to new stimuli or recall reactions to stimuli it already encountered.
But a Drexel research team led by Felice Elefant, PhD, an associate professor of biology, found that if they added extra Tip60 HAT in the brain of flies that displayed symptoms close to Alzheimer’s disease, the balance between the enzymes could be restored. When that balance came back, behaviors the team had taught the flies were able to be learned again and remembered. Elefant’s PhD student, Priyalakshmi Panikker, was lead author on the study, which also included other Drexel graduate and undergraduate student collaborators.
“Our findings strongly support the concept of exploring the efficacy of specific Tip60 HAT activators, as well as identifying and manipulating additionally misregulated Tip60 target genes,” Elefant says.
For the study — part of a five-year, $1.96 million grant awarded to Elefant from the National Institutes of Health — flies were conditioned to move toward a certain odor associated with sucrose, a positive reinforcement for them. After being exposed to the scent paired with sugar, the flies learned to move toward the scent even without the sugar present.
Flies that modeled Alzheimer’s disease later showed no reaction to the smell, demonstrating that their ability to remember the association was negatively affected.
But once Tip60 HAT was introduced in the brain to correct the Tip60 HAT/HDAC2 imbalance, these flies showed a reac- tion time comparable to the control population. This indicated that they recovered their ability to learn and remember after the epigenetic balance was reintroduced. The added Tip60 HAT also restored function in nine out of 11 brain function-related genes that were repressed by the elevated HDAC2 levels.
“Many researchers who study Alzheimer’s disease utilize human post-mortem samples, and thus, they are not looking at what is happening during the early progression of neurodegeneration, including whether we can correct what is happening during these early stages,” Elefant says.
The results of the study, which were published in the Journal of Neuroscience and promoted by publications like Newsweek, were encouraging. Elefant’s goal is to find new avenues for gene therapy.
“When people age, they have a loss of memory, but it’s not because there are mutations in their genes,” Elefant says. “It’s the way the genes are packaged. They’re distorted. And we’re seeing non-invasive ways we might be able to prevent that early on.”