Professors earn grant to find key, unlock Alzheimer's

What if you could turn on a “vacuum cleaner” and remove molecules associated with Alzheimer’s disease from the brain? That’s essentially what two ASU professors are exploring.

Carl Wagner and Peter Jurutka, faculty members in ASU’s New College of Interdisciplinary Arts and Sciences, have earned a $750,000 grant to conduct drug discovery research related to Alzheimer’s disease.

The grant, awarded by Bank of America, acting as a trustee of the Thome Memorial Foundation, will be shared with researchers at Case Western Reserve and the University of South Florida. The interdisciplinary three-year project combines synthesis, cell-based assays and testing of novel molecules that may have the potential to treat Alzheimer’s disease by reducing or removing the amyloid beta plaques in the brain that are thought to contribute to the degenerative disease. Wagner and Jurutka, who teach in the New College Division of Mathematical and Natural Sciences, will focus on the synthesis and cell-based testing of the molecules.

“Our research is focused on trying to find a way to ‘turn on’ genes in the brain that result in an increased rate of clearance of amyloid beta, so it does not form plaque and kill brain cells,” said Wagner, an assistant professor who earned his doctorate in organic chemistry from the University of California, Irvine, in 2003 and came to ASU’s West campus in 2006. “The anti-cancer molecules I have been making, and Peter has been testing, may have the potential to treat Alzheimer’s disease, as well as various cancers.”

Gary Landreth, director of the Alzheimer's Research Laboratory and a professor of neurosciences and neurology at Case Western, has recently discovered that the molecule bexarotene results in a reduction of amyloid beta plaques – a sticky protein fragment that accumulates in the brain of patients with the disease – in mouse models of Alzheimer’s disease by 60 percent to 65 percent. Wagner said the significance of that discovery is that bexarotene is already an FDA-approved molecule and could be used off label to treat Alzheimer’s. Now, the two New College professors will explore the creation of new molecules similar to bexarotene to see if they have a comparable effect, or even a better effect in reducing amyloid beta plaques.

“Think of it this way: The bexarotene molecule is a key, and it fits in a ‘lock’ that results in turning on the genes that cause amyloid beta clearance," said Wagner, who has been making analogs of bexarotene since 2006. “We are trying to develop a better key for the lock.”

Wagner and Jurutka, who joined the New College faculty in 2004 and recently received a $1.5 million NIH R01 grant to research answers relative to cancer, have collaborated on a number of drug discovery projects while at ASU. Jurutka said the Thome grant is an opportunity to bridge the organic synthetic chemistry work being done in Wagner’s lab with the cancer biology research conducted by his group. Wagner builds molecules from simpler ones using known organic synthetic chemistry. The worth of those molecules is validated by Jurutka’s evaluations.

“Once Carl synthesizes a bexarotene analog, our lab must evaluate the ability of that bexarotene-like molecule to serve as an effective possible drug,” explained Jurutka. “Thus, we must test the ability of the compound to bind to certain receptors in human cells, we must evaluate its potential to activate genes, and we must appraise the biological potency of the drug.

“Essentially, this is what’s involved in the assessment of a bexarotene analog ‘key’s’ ability to fit into the ‘lock’ and turn on the genes that clear beta amyloid.”

The analogs that display the most favorable properties in these tests are candidates for further testing, which will be performed by the Landreth-led team at Case Western. Another collaborator, former ASU assistant professor of chemistry and biochemistry Arjan van der Vaart, will perform computer models throughout the research process from his lab at the University of South Florida.

As the ASU team seeks a molecule similar to bexarotene that may be more effective at a lower dose with fewer potential side effects, Jurutka said the research being conducted in the New College labs holds the promise of providing more treatment options to choose from before clinical trials.

“Recent studies on this horrible disease have not only provided striking new insight into the pathophysiology of Alzheimer’s disease,” he noted, “but have also provided compelling support for the development of new drugs that can help ‘jump start’ the sluggish process of amyloid beta plaque clearance in these patients, which is exactly what our new drug discovery research proposes to do.”

Wagner said his collaboration with Jurutka has additional benefits.

“Our collaboration has been extremely productive in that it has not only generated research funding, but we have trained and mentored a number of talented ASU undergraduate students over the years. These are students we believe will be at the forefront of the next generation of researchers who will continue to advance our knowledge in drug discovery research.”

ASU’s New College of Interdisciplinary Arts and Sciences prepares its students to take their place as independent thinkers and active participants in the shaping of society. The college's diverse curriculum offers students the opportunity to design an individual course of study, to explore an interdisciplinary major, or enroll in a more traditional liberal arts and sciences program. New College offers programs emphasizing experiential learning that spans academic disciplines, enhances appreciation of all forms of creative activity, and empowers student achievement in the humanities, the arts and the sciences.