_HEALTH MEDICINE Biology

_Cracking Alzheimer’s

With the help of the tiny, remarkable fruit fly, two Drexel researchers aim to speed up science’s understanding of a disease that affects more than 5 million Americans.

_Aleister Saunders

Saunders is an associate professor of biology and director of the RNAI Resource Center and associate dean for research and graduate education in the College of Arts and Sciences. His laboratory focuses on identifying and characterizing genes involved in the pathogenesis of Alzheimer’s disease.

_Daniel Marenda

Marenda is an assistant professor of biology, co-director of the Cell Imaging Center and director of the biology graduate program in the College of Arts and Sciences.

Two Drexel University scientists have developed a powerful Drosophila model to study better the progression of Alzheimer’s disease as well as to screen in a quicker and cheaper fashion potential drugs.

“We set out to create a new model,” says Aleister J. Saunders, an associate professor of biology and associate dean for research who has long studied the neurodegenerative condition on the human cellular level. In recent years, he has collaborated with Daniel R. Marenda. The assistant professor of biology and co-director of the Cell Imaging Center is known around campus as the “Pied Piper of Fruit Flies” because of his enthusiasm for the Drosophila disease model.

Alzheimer’s, the most common cause of dementia in the developed world, afflicts 5.4 million Americans. In the next 50 years, that number is expected to skyrocket to 16 million.

In humans, the disease is characterized by amyloid plaques and neurofibrillary tangles of the brain matter. The hippocampus and cerebral cortex regions suffer loss of neurons and shrinkage. As the β-amyloid plaques accumulate from the processing of amyloid precursor protein (APP), they are believed to interfere with the communication between neurons across synapses. Ultimately, that results in cell death and loss of memory.

Marenda and Saunders’ new model intentionally over-expresses the human forms of APP and the BACE gene, also involved in the formation of plaques. That novel approach, published in 2011 in the journal PLOS ONE, allows flies to develop Alzheimer’s in a way similar to what occurs in humans. “What we’re doing is recreating the pathology and behaviors associated with Alzheimer’s,” Saunders says.

Animal models like this one are crucial to understanding how diseases work because studies in artificial environments (in vitro), while perhaps more efficient, do not always reflect the complexity of organisms.

There are, of course, other animal models to study Alzheimer’s, including the popular mouse one. But Saunders and Marenda argue that Drosophila has the advantage of price tag and time. They estimate that mouse models can cost at least 100 times more than fly ones. In addition, it can take three months to detect Alzheimer’s in the mouse compared to at birth for the adult fruit fly (following a two-week gestation period).

Drosophila is a living creature,” Saunders says, “and you can get results in days instead of months.”

Fruit fly models with the human forms of APP and BACE also exist, but they target the fly’s developing retina and wing tissues. “We decided to look not just at the eye or wing but everywhere in the central nervous system,” Saunders says. “That was our twist on this.” (Recently, another team expressed APP and BACE in a fly model but it does not appear as robust as the Drexel one – taking much longer for changes in the anatomy of the fly’s brain to appear.)

Another distinguishing feature is the way Alzheimer’s is introduced to the fly. The researchers have inserted raw materials – the proteins associated with the disease – and allowed them to take their course naturally, Marenda explains.

“Ours is different because we’re letting the fly perform the normal biological functions that have to occur in the neurons in order for the plaques to form,” he says. “There are no other fly models that express Alzheimer’s disease in the way this does.” This is important when investigating ways to arrest the disease progression in its earliest stages.

This is a robust model for several reasons. It accurately reflects within days the changes in the brain and cognitive defects that characterize Alzheimer’s in patients. The flies also show characteristics outside the brain – crumpled wings and black masses on the abdomen and proboscis. In addition, the flies respond to drugs intended to suppress the disease’s progression, making it an ideal vehicle for rapid screening and testing of small-molecule compounds. The model is available to other labs.

Like many good innovations, this one began with serendipity and required perseverance. Back in 2007, Marenda was at the University of the Sciences in Philadelphia working on fruit flies. While visiting Drexel to consult with a geologist about a suspected meteorite fragment (it’s a long story), he was introduced to Saunders as a Drosophila guy.

Soon, the two combined their talents. Saunders was the Alzheimer’s expert on the cellular level, and his lab was discovering genes that regulate a central process in the disease. He was using cancer cells in his studies – a common protocol. But, Saunders says, “they have nothing to do with the 70-year-old brain of a human. I knew that. I always saw the fly as a great model system.”

But he didn’t know much about the mechanics. Marenda did. With the support of a $1.7 million NIH grant, the two used genetic techniques to express proteins related to Alzheimer’s in the central nervous system of the flies and compared them to normal flies.

“We start with human biology, looking at the symptoms the humans are exhibiting,” Marenda says. “Then we determine whether or not the animals we’re using recapitulate those systems well.” If they do – and they did – then that suggests the processes occurring in the flies are comparable to what happens in people. (On the genetic level, flies and humans share an incredible 80 percent of disease genes related to intellectual disabilities.)

Once the model was created, it needed to be tested for viability – did the flies experience the critical symptoms of Alzheimer’s? Loss of memory, of course, is a hallmark of the condition, but how do you test a fruit fly’s memory? Courtship behaviors, it turns out.

Flies are naturally skilled at mating. In the study, a healthy male fly isolated from birth (to avoid any social cues from other flies) was introduced at his sexual peak (three to five days after birth) to a female fly that had already mated. She wasn’t interested in his advances, and she made that clear by flicking him with her wings and kicking him in the head. Remember, female flies are larger than male ones, so the pounding was sure-to-be memorable.

She also zapped him with nasty pheromones. Over an hour, the poor guy got the message – better to avoid courtship.
Two minutes later (the window for very short-term memory in flies), the male fly was then introduced to another female fly, this one unmated and open to advances. “If a normal fly can remember its training, it will have a suppressed courtship response,” Marenda says.

That’s exactly what happened.

The same experiment was repeated with an Alzheimer’s disease (AD) fly. “The AD flies can learn,” Marenda says. “It’s their memory that is compromised.”

Like its healthy counterpart, the AD fly learns to abandon courtship behaviors. But after the two-minute wait, the AD fly does not remember the painful wallops and rejection he experienced at the wings and legs of the female.

“AD flies will court the female flies just as vigorously as if they had not been trained,” Marenda says.

Autopsies of these flies confirm build-up of plaques and shrinkage of the portion of the brain responsible for memory – the same features found in human post-mortems.

Finally, the researchers decided to test whether a drug (an ϒ-secretase inhibitor) known to stop the production of the plaques would work in the model. (This drug is not practical in humans because it can lead to cancer.)

It did. The AD flies with cognitive deficits, including one involving a slowdown in climbing behavior, improved.

“We’ve cured Alzheimer’s disease – if you’re a fly,” Saunders says.

With Drexel’s robust Drosophila model now available, researchers may one day be able to find the same success in humans.