A new therapy busts up deposits of sticky plaques associated with Alzheimer’s disease in the brains of mice. Further tests with the experimental drug could help settle the question of how important the plaques are to the disease, and might even lead to a treatment for its most advanced stages.
The study, described in the Dec. 6 Neuron, tested an antibody called mE8 in the brains of older mice that had been genetically altered to accumulate amyloid-beta, a protein that forms plaques in the brains of people with Alzheimer’s. “We removed 50 percent of the plaque,” says study coauthor Ronald DeMattos of Eli Lilly and Co. in Indianapolis. “This is a big deal.”
The scientists haven’t yet looked for any behavioral improvements in the mice. Nor is it clear that the drug would work the same way in people. But DeMattos and his Lilly colleagues are hopeful that the therapy will lead to new treatments for patients in later stages of Alzheimer’s, who carry large amounts of plaque in their brains.
Other researchers say that busting plaques may be the wrong approach to slowing or stopping the dementia that plagues Alzheimer’s patients. Another antibody recently failed to change the course of Alzheimer’s disease in two large clinical trials. Although the drug developers haven’t yet released the full details of those trials, that antibody — called bapineuzumab — appears to reduce levels of A-beta and shrink plaques. But with no improvement in symptoms, the trial results, reported in August, are a setback on the path to new Alzheimer’s drugs.
The new findings show that mE8 sidesteps a complication seen with bapineuzumab: The new antibody didn’t cause tiny leaks in brain blood vessels, the study authors report. This bleeding can damage brain tissue, which could lead to mental deficits. To neuropathologist Rudolph Castellani, the failure of bapineuzumab adds to a long list of evidence showing that clearing out plaques is just a bad strategy. “The bottom line is there’s no meaningful benefit of removing plaques,” says Castellani, of the University of Maryland School of Medicine in Baltimore. Testing the idea again won’t help. “We’ve been to this movie before, and we know how it ends.”
DeMattos counters that earlier antibodies, including bapineuzumab, couldn’t discriminate between free-floating A-beta and A-beta embedded in plaques. So those antibodies might have been sidetracked by the free-floating form and not been able to effectively combat plaques. In contrast, the new antibody was designed to ignore free-floating A-beta and target only the plaques. This ability to hit the plaques hard may prove therapeutic, DeMattos says.
But neuroscientist Thomas Wisniewski of New York University School of Medicine, and many other scientists, now believe that the dangerous form of A-beta is not the hulking plaques, but rather much smaller forms of A-beta called oligomers. “Plaques are bad, but we’re all thinking oligomeric A-beta is worse,” says Wisniewski, who has served as an expert witness for Eli Lilly.
DeMattos contends that getting rid of the plaques could clean up oligomers and other A-beta in the surrounding areas, too. Because plaques serve as storage units for A-beta, the protein may jump on and jump off the plaques — potentially producing a harmful cloud of A-beta, akin to the dirt surrounding Charlie Brown’s friend Pig-Pen. So shrinking the plaques could lead to an overall improvement in brain function, says DeMattos. “You’re going to remove this big reservoir.”
R.B. DeMattos et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron, Vol. 76, December 6, 2012, p. 908. doi: 10.1016/j.neuron.2012.10.029. [Go to]
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