Medical researchers have successfully treated Alzheimer’s disease in mice by putting drops of vaccine in their noses. They think it will ultimately be possible to do the same with people.
“We plan to begin human trials next year,” says Howard Weiner, a neurologist at Harvard Medical School who has pioneered the use of oral and nasal vaccines.
Other scientists have begun giving an injectable form of the same type of vaccine to Alzheimer volunteers in the United States and United Kingdom. These tests will determine if the vaccine can be safely given to humans.
Three different research teams in Tampa, Fla.; Canada, and Scotland reported last month that similar injections delay memory and learning problems in mice genetically engineered to get a humanlike form of Alzheimer’s.
“These studies open up the possibility, not only of treating Alzheimer’s, but of preventing it by injection or nasal spray,” says Dennis Selkoe, a Harvard Medical School neurologist who collaborated with Weiner on development of the nasal vaccine.
In 1993, Selkoe and Weiner got together over dinner to talk about how they might combine their expertise to find a better treatment for a disease that robs more than 4 million Americans of their cognition and personalities. Selkoe has spent much of his research career trying to understand how Alzheimer’s destroys a person’s brain. For the past 15 years, Weiner has been developing oral and nasal vaccines for diseases such as multiple sclerosis, rheumatoid arthritis, and diabetes.
They decided to fight Alzheimer’s with the same protein that seems to cause it. The brains of Alzheimer’s victims accumulate millions of round microscopic gobs of a sticky substance known as amyloid-beta. These “plaques,” as they are known, are thought to lead to the destruction of nerve cells in parts of the brain responsible for memory and thinking.
Weiner and Selkoe came up with the idea of giving small amounts of amyloid-beta by nose or mouth to stimulate an immune-system response against the disease. This strategy might work somewhat like an oral polio vaccine, which primes the immune systems to make white blood cells and proteins that hunt down and destroy the polio virus.
Making clear-headed mice
The first step was to obtain mice genetically engineered to have the human gene that produces amyloid-beta. In nine to 12 months, the brains of such rodents become peppered with plaques, structurally and chemically similar to those in a human brain. Working with colleagues Cynthia Lemere and Ruth Maron, Selkoe and Weiner gave the mice amyloid nose drops every week for seven months.
The team then painstakingly counted plaques in the mice and compared the numbers with other mice born to get Alzheimer’s but left untreated. There was a dramatic difference. The vaccinated mice had about 50 percent fewer plaques.
A third group of mice who got the same vaccine by mouth showed little or no improvement; the researchers do not yet know why.
The findings reinforced those obtained by different researchers who gave mice an amyloid vaccine by injection. In the latter experiments, conducted by Dale Schenk of Elan Pharmaceuticals of South San Francisco, the treated mice had about 90 percent fewer plaques in their brains compared with those who received injections of salt water.
The Harvard researchers don’t think that the difference in the amount of plaque reduction is a problem. “We tried only one dose amount and gave in only once a week,” Weiner points out. “We plan to give two different doses during the human tests, and we can increase their frequency.”
“Based on our mouse study, we now know the nasal route is effective in producing a beneficial response to the amyloid-beta,” Selkoe adds. “Using an inhaler should be easier and more pleasant than receiving multiple injections, especially for older people. We also believe an initial injection followed by a nasal booster might prove useful.”
Clearing a brain of sticky plaque deposits seems like a major victory, but does it really change behavior for the better? Two groups of researchers who recently set out to answer that question say that it does. They ran both vaccinated and untreated Alzheimer mice through various tests, such as determining how well they remember the right path through a maze. Paws down, the treated mice did much better.
Dave Morgan and his colleagues at the University of South Florida reported last month that “vaccination with amyloid-beta protects (genetically engineered) mice from the learning and age-related memory deficits that normally occur in this mouse model for Alzheimer’s disease. … At an age when untreated mice show memory deficits, the vaccinated mice exhibited superior cognitive performance.”
Taking a vaccine to heart
Before trying the nose drops in people, there are a few loose ends the Harvard group would like to tie up. “We are attempting to develop a stronger response to the vaccine without compromising safety,” Selkoe explains. “We also want to find out exactly how the vaccine works.”
It is thought that the vaccine works somewhat like a flu shot; that is, it generate antibodies, proteins that find and attach themselves to amyloid plaques the way flu antibodies attach to viruses. At the same time, other cells seem to home in on the tagged antibodies and eat away the amyloid. Yet other cells may attack the plaques directly.
“That’s only a general description of what could happen,” Selkoe admits. “We need to pin down all the specifics.”
Once antibodies and other cells “scavenge the amyloid-beta protein, the inflammation that damages brain cells is markedly reduced,” Weiner adds.
Since he originated the idea of oral vaccines for immune-system diseases some 15 years ago, Weiner and others have tried them on many different ailments. Human tests are now underway of an oral vaccine for multiple sclerosis. Some 1,600 patients are involved in tests going on at a number of sites, including Brigham and Women’s Hospital in Boston, where both Weiner and Selkoe work.
An oral vaccine to prevent juvenile diabetes is being given to several hundred children in various centers throughout the United States. This trial is sponsored by the National Institutes of Health
Inflammation in Alzheimer’s and multiple sclerosis share similarities with plaques and inflammation associated with thickening and blocking of human arteries. Weiner and Ruth Maron are collaborating with Peter Libby at Brigham and Women’s Hospital to test a nasal vaccine on mice engineered to develop dangerously high levels of cholesterol. Results so far are encouraging. Vaccinated mice boast smaller plaques in their arteries than their unvaccinated cage mates.
“Our results,” Weiner concludes, “suggest a new immunologic approach for the treatment of atherosclerosis.”