Lowering beta-amyloid levels in blood to treatment Alzheimer’s

Agents that alter blood levels of beta-amyloid protein in mouse models of Alzheimer’s disease represent a potential approach to treating the illness in humans that may be safer than the vaccine method of therapy, researchers report in a new study.

Beta-amyloid protein is a component of the amyloid plaques that accumulate in the brains of people with Alzheimer¡’s disease. Beta-amyloid is viewed by many researchers and clinicians as the underlying cause of the degeneration and dementia that characterize the illness. Alzheimer’s disease is a progressive, degenerative brain disease and the most common form of dementia. There is no cure. Approximately four million Americans have the disease and some 14 million are expected to have it by 2050 unless a cure or preventive treatment is found.

“Recent evidence suggests that this protein in the peripheral circulation outside the brain may contribute to its accumulation in the brain,” says study co-author Karen Duff, PhD, of the Center for Dementia Research, Nathan Kline Institute/New York University. The study, funded by the National Institutes of Health and the Alzheimer’s Association, appears in the January 1 issue of The Journal of Neuroscience.

If Alzheimer’s disease can effectively be treated by agents that do not need to enter the brain, pharmaceutical companies may be able to develop targeted drugs that have few effects on the central nervous system, she adds. Previous animal studies suggested that one way to do this was through a vaccine that produced antibodies to amyloid. But Elan Corporation and American Home Products ended trials of their immune-based Alzheimer’s vaccine in February 2002 after 15 patients experienced swelling of the central nervous system.

“There’s good medical precedent seen in the treatment of coronary heart disease by administering agents that lower serum cholesterol levels,” notes Bradley Hyman, MD, PhD, a neurologist at Massachusetts General Hospital in Boston. “This kind of parallel approach ¨C blocking beta-amyloid accumulation in the brain by binding it to an agent in the bloodstream ¨C represents an extremely viable line of research.”

Other scientists, however, suggest the results of such studies be viewed with caution. “Having a substance that acts as a peripheral sink for brain beta-amyloid may simply be shifting the damage from the brain to the vasculature and body itself,” says Gary Arendash, PhD, professor of biology and psychology at the University of South Florida. “This approach may trap a considerable amount of beta-amyloid in the cerebral blood vessels, weakening them and leading to cerebral hemorrhage.”

In the new study, Duff, Dr. Yasuji Matsuoka and their colleagues injected the beta-amyloid binding agent gelsolin into the peripheral bloodstreams of 13 mice bred to develop Alzheimer’s disease. They also performed sham injections in 16 other mice with the same genetic background. Both groups received injections every two days for three weeks. Upon examination, the brains of mice receiving gelsolin had significantly less beta-amyloid protein than those in the other group. Use of gelsolin also resulted in a significant decrease in the number of brain plaques.

The scientists saw similar results when they used another beta-amyloid binding agent, ganglioside GM1.

“We do not advocate using these particular agents as treatments for Alzheimer’s disease in humans,” Duff says. “Rather, we see this as an initial step in the development of compounds that act in this manner, and as proof-of-concept for a prophylactic approach that may be more flexible, more reliable and less likely to cause side effects in long-term administration paradigms than immunization-based therapies.”

Duff and Matsuoka’s colleagues in this study include: Mariko Saito, Mitsuo Saito, John LaFrancois, Kate Gaynor, Vicki Olm, Lili Wang, Evelyn Casey, Yifan Lu, Chiharu Shiratori and Cynthia Lemere. Duff, Matsuoka and Lemere are members of the Society for Neuroscience, which publishes The Journal of Neuroscience. SfN is an organization of more than 31,000 basic scientists and clinicians who study the brain and nervous system. Duff can be reached at 845-398-5427; Matsuoka can be reached at
845-398-2175.