Antibodies to fight Alzheimer’s may have unexpected consequences

Treatment that targets amyloid-beta plaque buildup makes mouse nerve cells hyperactive

In an unexpected twist, two antibodies designed to fight Alzheimer’s disease instead made nerve cells in mice misbehave more.

The results, published online November 9 in Nature Neuroscience, highlight how little is known about how these drugs actually work, says study coauthor Marc Aurel Busche of Technical University Munich. “We need to understand what these antibodies do in the brains of patients better,” he says.

The treatment approach relies on antibodies that target amyloid-beta, a protein that builds up in the brains of people with Alzheimer’s. One of the antibodies used in the new study, bapineuzumab, failed to show benefits in much-anticipated trials described in the New England Journal of Medicine in 2014.

Despite that setback, some researchers say antibodies are still the best option to halt Alzheimer’s. The bapineuzumab trial was flawed, says neurologist Dennis Selkoe of Harvard Medical School and Brigham and Women’s Hospital. And the new results, which come from mice, have little relevance for ongoing tests of other antibodies in people, he says.

“A-beta immunotherapy is the most promising approach right now, and nothing in their paper undercuts that,” he says. Several other antibodies have recently shown modest benefits in people with Alzheimer’s, he adds. Representatives from Eli Lilly and Biogen, pharmaceutical companies that are developing antibody treatments, declined to comment on the new study.

Busche and his colleagues found that a single injection of the mouse version of bapineuzumab caused nerve cells in the brains of mice designed to produce A-beta to become hyperactive. In some cases, treatment caused the nerve cells to fire off messages in tandem, an unusual form of neural synchrony that’s been linked to seizures. Injections of beta-1, another antibody that has not been developed into a drug, also made nerve cells hyperactive. Neither antibody had an effect on nerve cells in normal mice that didn’t produce A-beta, suggesting that the hyperactivity depends on the combination of antibody and A-beta.

Questions remain, and the results don’t mean that clinical trials of antibodies should stop, Busche says. It’s unclear how the antibodies stir up neural trouble in mice, and whether this hyperactivity relates to behavior problems. (The scientists didn’t test the mice’s behavior.) One of the biggest questions is whether A-beta–targeting antibodies cause nerve cells to become hyperactive in people — a question not being asked in clinical trials.

For now, Selkoe says that the result is interesting preclinical science. “We wouldn’t want to ignore it,” he says. “But I think it has little relevance to the current state of antibody treatment development in humans.” 

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