German researchers are reporting a new approach to the possible prevention of the molecular "debris" that's associated with the development of Alzheimer's disease.
A number of laboratories, both academic and commercial, are working on methods to prevent the enzyme from slicing a protein into beta amyloid fragments that form the brain plaques found in people with the disease. All work on the same principle. "If we decrease the amount of cleavage, we could in all likelihood reduce the likelihood of the disease," Simons said.
Most experts now agree that formation of the beta amyloid plaques is directly linked to the development of Alzheimer's. The problem with most proposed methods of blocking beta-secretase, Simons said, is that they are designed to work outside of the affected brain cells.
"This process of cleaving takes place inside cells," he said. "We have constructed an inhibitor which binds outside, on the cell membrane, and goes into the cell where the cleavage occurs."
Reporting in the April 25 issue of the journalScience, Simons and his colleagues described both test-tube experiments and animal studies in which the combination of an anchoring molecule and a beta-secretase inhibitor reduced the formation of beta amyloid plaque by more than 50 percent over four hours, while the inhibitor alone was ineffective.
The success is just one small step toward a medically useful preventive therapy for Alzheimer's disease, Simons acknowledged. For one thing, the treatment was given by injection into the brains of the experimental animals (fruit flies and mice), something not likely to be done with people.
"This is proof of principle," Simons said. "The idea would be to get it into the blood in humans and then over the blood-brain barrier into the brain. There are many ways for molecules to get into the brain."
The blood-brain barrier is a network of tightly packed cells that prevents most molecules from entering the brain.
William J. Netzer, an Alzheimer's researcher at the Fisher Center for Alzheimer's Disease Research Foundation at Rockefeller University in New York City, called the new study "a profoundly interesting line of research."
"It is not implausible that one might improve the effectiveness of a drug by coaxing it to go into a region where the enzymes it blocks exist," Netzer said.
But medical use of such a product can raise questions, he said. "When you put an inhibitor into a living being, the chemical you put in can be modified in the body. Where a compound goes into a cell is a complicated issue when you put it into a human being," he added.
Dr. James Galvin, associate professor of neurology and psychiatry at Washington University in St. Louis, called the German research "a novel idea."
If the concept works, it would solve a puzzle about how to best target the enzyme, Galvin said. And it is a concept with broader medical possibilities, he said.
"You can potentially inhibit other enzymes where cleavage occurs within membranes," he said.