|image: Elan Corporation|
For the more than four million Americans who suffer from Alzheimers disease, the news last year of a vaccine in mice that could stop the formation of plaques in the brain associated with the disease offered new hope. But some scientists wondered if the vaccine might do more harm than good.
Now two independent studies published in this weeks journal Nature show that when given to mice, the vaccine can halt the progression of memory lossone of the major hallmarks of the disease.
When they began their research, scientists at the University of South Florida were actually setting out to prove that the vaccine, developed last year by Elan Pharmaceuticals, would cause memory deterioration. They were concerned that it might provoke an immune response that could end up causing the very memory loss it was designed to prevent.
|The white mouse at the left side of this pool hasnt found the hidden underwater platform (red arrow).|
image: WSTF, Tampa
But the opposite turned out to be true. Researchers tested mice genetically engineered to develop Alzheimers disease to see how well they performed in a water maze using a hidden platform whose location they were required to learn. "All the mice we gave the vaccine to were able to learn this task, none of the mice that we did not give the vaccine to were able to learn this task," says David Morgan, lead author of the study. "So, not only did we not find what we thought we would findthat is, a premature memory lossbut we in fact found that the vaccine completely protected these mice from developing the memory loss that they otherwise would have."
To test whether the vaccine might cause memory loss, Alzheimers mice were tested after theyd been inoculated for several months but before memory deterioration was expected to begin (11.5 months). They performed as well as controls. When they were tested at 15.5 months (roughly equivalent to a person in his or her early 60s) however, an age when they would have been expected to have memory deficits, they still didnt show any, whereas Alzheimers mice that were not vaccinated did show such a loss.
Scientists at the University of Toronto reported similar results. Using a different mouse model and different timing of the vaccine, researchers led by Peter St. George-Hyslop reported improved memory in vaccinated mice with the Alzheimers gene.
Its not brain surgery
|ß-amyloid deposits are seen as brown spots in the mouse brain tissue on the left. The deposits were eliminated by treatment with the vaccine as seen on the right.|
image: Elan Corporation
The vaccine, developed by Dublin-based Elan Pharmaceuticals, caused quite a stir when it was first reported in Nature in July, 1999. It was shown to prevent the build-up of amyloid plaquesprotein fragments that form sticky buildup in the brains of Alzheimers patientsin mice engineered to have the disease. Along with neurofibrillary tangles, amyloid plaques are thought to cause damage to neurons in the brain and thus lead to the symptoms of Alzheimers disease.
Although the vaccine began to be tested in humans last year, Elan had no way of knowing whether it actually reduced memory loss in the mice, or just helped eliminate plaques. There was even a chance it could worsen the disease.
Because the vaccine consists of an injection of the same proteinbeta amyloidthat causes the plaques in the first place, Morgan and other scientists were concerned that it might cause an immune reaction that could lead to inflammation that would kill brain cells. In fact, it is not known whether Alzheimers symptoms are caused by the plaques themselves or the immune systems reaction to beta amyloid.
"We thought that the vaccine itself would be something you shouldnt be putting into human beings," says Morgan. "We wanted to demonstrate with our mouse model that it caused a premature memory loss, that this loss of memory would in fact be indicative that activating the immune system in the brain is not something that you want to do."
Morgan says he was prepared to try and halt the human trials, but now favors them. Last July, Elan reported at the World Alzheimers Congress that trials in humans have so far shown the vaccine to be safe. Those wanting to enter clinical trials should be aware that while some patients could be the first to experience the benefits of the new vaccine, others will receive a placebo, which has no effect.
If the thought of a needle is less than appealing, new research has shown that there may be other ways to deliver the vaccine. Researchers at Harvard Medical School reported that a nasal vaccine against Alzheimers tested in mice could also reduce amyloid plaques. The results were published in the October issue of Annals of Neurology. While the nasal application, which works like an asthma or allergy inhaler, was not quite as effective as the injections, it may prove to be easier to administer in the long term.
The next step, at least for Morgan, is to find out if the vaccine can reverse memory loss. By testing Alzheimers mice at 15 months to show that they have already developed memory loss, vaccinating them for several months, and then retesting them, he expects to be able to tell if the loss has been reversed. "If were able to do that, Ill be flabbergasted," says Morgan. "That will tell me that this treatment really is a true miracle in the possible treatment of Alzheimers disease."
Elsewhere on the web
National Institute on Agings Alzheimers Disease Centers Program Directory
Alzheimers Disease Clinical Trials Database
Alzheimers Disease Education Referral Center
NIH 1999 Progress Report on Alzheimers Disease
The Brain and Alzheimers Disease