The study, conducted by researchers at Washington University School of Medicine in St. Louis and Eli Lilly and Company, used an antibody that targets a particular region on the amyloid-beta protein. The amyloid-beta protein accumulates in the brain to form the amyloid plaques, a major feature of Alzheimer’s disease. The study is published in the July 3 issue of the Proceedings of the National Academy of Sciences Early Edition.
"We think the antibody is drawing amyloid-beta out of the brain and into the blood as a clearance mechanism," says senior author David M. Holtzman, M.D., associate professor of neurology at the School of Medicine. "Within hours of injecting the antibody into mice, the concentration of amyloid-beta in the bloodstream rose approximately 1,000 times higher than it had been before the injection. The antibody was binding all the amyloid-beta in the blood as well as additional amyloid-beta as it entered the blood from the brain. Since most of the amyloid-beta in the blood is derived from the brain in these mice, the antibody appeared to be facilitating the removal of amyloid-beta from the brain into the blood."
The team’s results support this theory since animals injected with the antibody over a period of months developed fewer amyloid plaques in the brain than did control animals.
The researchers found that after injection, the antibody m266 remained in the animals’ bloodstream and did not react directly with amyloid plaques in brain tissue. Typically, very little antibody in the blood (less than 0.1 percent) enters the brain or cerebral spinal fluid, the fluid that surrounds the brain. Nonetheless, the antibody, in addition to causing an increase in amyloid-beta in the blood, also transiently increased the amount of soluble amyloid-beta protein in the cerebral spinal fluid. "Our work is distinguished from previous research in that we have discovered that this particular antibody can be administered into the bloodstream and need not necessarily gain access to the brain and directly attack amyloid plaque to be effective in reducing plaques," says co-investigator Steven M. Paul, M.D., group vice president at Lilly Research Laboratories. "Thus, our work suggests a new mechanism by which certain anti-amyloid antibodies could be useful in preventing or treating Alzheimer’s."
The experiment involved two control groups of mice that received injections of either saline or a control antibody and a group of mice that received m266 antibody injections. The injections were administered every other week beginning at four months of age. At nine months of age, each mouse was examined for plaque development. In the control groups, about 40 percent of the animals had developed significant amounts of amyloid plaques. Only about seven percent of the mice in the m266 antibody-treated group developed significant plaques.
The difference between the two control groups and the group receiving the antibody was statistically significant.
The research team now is working to understand the detailed mechanism of how the antibody exerts its effect. The research has potential implications for both diagnosis and treatment of Alzheimer’s disease.
DeMattos RB, Bales KR, Cummins DJ, Dodart J-C, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease, Proceedings of the National Academy of Sciences Early Edition, 2(27), July 3, 2001.
Eli Lilly and Company funded this research and provided the reagents for this study.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Lilly, a leading innovation-driven corporation, is developing a growing portfolio of best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers – through medicines and information – for some of the world's most urgent medical needs. Additional information about Lilly is available at www.lilly.com.
Journal
Proceedings of the National Academy of Sciences