Vaccine May Clear Alzheimer’s Brain Plaques

Nasal Spray Based on FDA-approved Drugs, Not Antibodies

Photo by Steve Gilbert From left, Dan Frenkel, Howard Weiner, and Ruth Maron were studying the relationship between Alzheimer’s and encephalitis when they uncovered a new vaccine strategy for Alzheimer’s.

While there is still no consensus about the role of waxy amyloid plaques that fill the brains of Alzheimer’s patients, many in the field believe they are a root cause of neurodegeneration and that clearing them may improve the cognitive function of patients. A major strategy has been to remove amyloid-beta by creating antibodies against it. But trials for an amyloid-beta vaccine were halted in 2003 when six percent of the patients developed life-threatening encephalitis. Since then, two follow-up studies provided some evidence that patients did benefit, raising hopes that a vaccine may work if side effects are limited. Another trial is under way to see if delivering amyloid-beta antibodies, rather than the peptide itself, can be effective and safer.

In the September Journal of Clinical Investigation, a team led by Howard Weiner, the Robert L. Kroc professor of neurology at HMS and Brigham and Women’s Hospital, unveils another vaccine strategy for Alzheimer’s disease that clears the build-up of amyloid plaques in a mouse model. The new strategy triggers cells of the immune system to gobble up amyloid-beta, sidestepping antibodies completely. It is delivered as a simple nasal spray, and consists of two FDA-approved drugs already in use for other conditions.

The vaccine emerged from a fortuitous discovery during an investigation of the role of the immune system in Alzheimer’s. After the problems with the -amyloid-beta vaccine, Weiner worked with postdoctoral fellow Dan Frenkel and Ruth Maron, assistant professor of neurology at BWH, to investigate the relationship between Alzheimer’s and an overactive immune system that would produce encephalitis. They wondered whether mice engineered to accumulate amyloid plaques, which serve as a model of Alzheimer’s disease, are more susceptible to autoimmune disease, and whether immunization with amyloid-beta causes autoimmune disease. They induced in the mice an autoimmune condition called experimental autoimmune encephalomyelitis (EAE), which is a common model of multiple sclerosis.

Pathology vs. Pathology
Contrary to their hypothesis, the mutant mice did not develop more severe disease than did controls, and no EAE was observed in mice immunized with amyloid-beta. But when the researchers examined the brains of the mice, they noticed something unexpected. Animals that had EAE showed far less amyloid-beta clogging their brains—94 percent less total content than control mice, and 86 percent less than mice that were immunized with a human amyloid-beta peptide.

It appeared that an MS-like syndrome somehow worked against the pathology of Alzheimer’s. “If you invoke a very strong inflammation in the brain, it clears the A-beta,” Weiner said. But more work had to be done to turn this finding into a therapy. As Frenkel pointed out, “You don’t want to induce one disease to cure another.” So the question was, Can we induce the clearance of amyloid without inducing disease? They found that antibodies, which have been the primary weapon of immune therapies for Alzheimer’s, were not playing a role in the clearance; the team reproduced the effect in mice that lacked antibody-producing B cells. Analysis of the tissue suggested that microglia, immune cells of the brain, were ingesting the excess amyloid and that targeting the microglia directly might be a better approach.

Repurposing MS Med
EAE can be induced by immunizing animals with one of several protein antigens found in myelin. It is thought that the proteins activate T cells in the body, which travel to the central nervous system and cause an autoimmune inflammation. About 30 years ago, researchers at the Weizmann Institute of Science in Israel synthesized a group of peptides in an attempt to replicate the actions of one of these antigenic proteins. Surprisingly, the concoction, called glatiramer acetate, had the opposite effect: it blocked EAE. Now, glatiramer acetate is widely used to treat relapsing MS.

Weiner’s team thought that glatiramer acetate might replicate the beneficial effects of giving mice a myelin antigen without causing inflammation. His lab is known for developing therapies that are delivered orally or nasally and work by activating the mucosal immune system, which he believes is a safer and easier way of delivering vaccines. The team administered glatiramer acetate nasally along with an adjuvant that would stimulate the mucosal immune system—in this case, one that is used for flu vaccines. Mice received four treatments the first week and a weekly booster for five weeks. With this combination, the researchers were able to reduce total amyloid levels in the brain by 73 percent without any signs of toxicity.

Dennis Selkoe, the Vincent and Stella Coates professor of neurologic diseases at BWH, said that in this study the researchers “show definitively for the first time that you don’t need to make antibodies to amyloid-beta” in order to clear it. Although the researchers do not yet know exactly how the vaccine works, Weiner believes that “the ultimate mechanism is activation of the microglia.” The team tested the vaccine on wild type mice and found that microglia were not activated when there were no amyloid-beta deposits in the brain. Because the vaccine uses two drugs that are already FDA-approved, Weiner is hoping that it can be moved into initial clinical trials sometime next year.

The big question about this strategy, as with the several other candidate drugs that target amyloid-beta buildup, is whether clearing plaques will truly cure disease. There is some evidence in animals and humans that removing amyloid may lead to cognitive improvements, but not enough to prove the case. Weiner believes that clinical trials of a therapy like this are the only way to know whether -amyloid--beta is the real culprit. “People can debate it for a long time,” he said. “The ultimate test is, if you clear it, do people get better?”

—Courtney Humphries

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