Aiming At Multiple Alzheimer's Proteins Key To Success
An independent team of scientists is leading Alzheimer's disease research in a new, promising direction. Through a $1 million grant they received last year from Alzheimer's Disease Research, a program of the American Health Assistance Foundation (AHAF), Donald F. Weaver, M.D., Ph.D. and his colleagues at Dalhousie University in Halifax, Nova Scotia, Canada are leading a multi-site, multidisciplinary international effort to design a drug that might one day prevent the onset of this devastating disease.
In Alzheimer's disease, an accumulation of beta amyloid protein "plaques" around the brain's nerve cells and tau protein "tangles" within these cells is connected to a breakdown in cell communication and eventual cell death. Evidence suggests that both beta amyloid and tau play a role, but the research community has been split on the relative effect of these two proteins on the disease process. Further, many scientists are beginning to believe that future Alzheimer's therapies will involve multiple drugs targeted at different aspects of the disease, including both of these proteins. They theorize that "misfolding" of each protein changes its shape and natural function, and contributes profoundly to the development of Alzheimer's disease. Dr. Weaver and his colleagues from Canada, the U.S., and Belgium agree that the key to successful treatment may be to halt the build-up of both beta amyloid and tau, before they begin to affect the brain's nerve cells.
"Alzheimer's disease is a complex ailment and may have overlapping causes," explains Dr. Weaver. "Disrupting beta amyloid misfolding may work for some people, but not others. The same is probably true for tau. If we could control both proteins in the same patient, we might get a synergistic benefit." Rather than seeking multiple drugs to accomplish this task, Dr. Weaver's team is looking for single molecules that will bind to both proteins and possibly other Alzheimer's-related proteins before they begin to misfold and start their toxic buildup. "Right now, we're treating the symptoms of the disease -- only slowing cognitive decline and memory loss in patients," says Dr. Weaver. "My colleagues and I are using this grant to design drugs that may one day prevent or even reverse progression of Alzheimer's disease."
The design strategy begins at Dalhousie University where researchers are creating new, unique drug compounds and testing each drug's ability to bind to both proteins and prevent shape changes. To date, Dr. Weaver's laboratory has produced more than 240 variations of the most effective compound. Once identified, these synthesized compounds are sent for further analysis to Edwin De Pauw, Ph.D. and his group at the University of Liege in Belgium. Promising compounds that pass this second step in testing then move on to preliminary safety and efficacy investigations using animal models in the laboratory of Ottavio Arancio, M.D., Ph.D. at Columbia University Medical Center in New York.
Since accepting the award from AHAF last year, this international team has made impressive progress. These easily reproducible chemical compounds have shown a remarkable ability to prevent misfolding of both proteins in the Dalhousie laboratory. This activity has been confirmed at the University of Liege, and exciting results are reported at Columbia. "Our lead compound is very effective in mice with conditions similar to Alzheimer's. It can be delivered orally, inhibits aggregation of these proteins, protects brain cells from beta amyloid damage, restores normal memory functioning and shows no toxicity at high doses," says Dr. Weaver. According to AHAF's Director of Research Grants, Guy Eakin, Ph.D., "This work is particularly important because Alzheimer's disease patients are often taking several medications for other health conditions. Rather than give them a 'cocktail' of drugs that might produce harmful interactions, Dr. Weaver's research shows it may be possible to limit these concerns by designing a single drug that tackles several factors."
This project has been substantially funded by one of two $1 million "Centennial Awards" from Alzheimer's Disease Research, a program of AHAF. To foster stronger collaboration among researchers, these unique awards were given only to scientists working with interdisciplinary colleagues at multiple institutions.