Nasal administration of synthetic beta amyloid peptide reduces potentially damaging Alzheimer's disease-like plaques in the brains of test mice and may one day be tested in clinical trials for its ability to vaccinate against plaque formation in people with Alzheimer's disease (AD), according to a new study by researchers at Harvard Medical School. The brains of the animals treated with the nasal spray had a significantly lower "plaque burden"—60 percent less in the hippocampus, for example—than mice that were not immunized or were treated with another protein, the scientists found. The findings are a significant step forward for the concept that an immunological approach, using vaccines, might one day be effective against Alzheimer's disease in humans.
The research is a collaboration of the laboratories of Howard L. Weiner, M.D., and Dennis J. Selkoe, M.D., at Harvard and Brigham and Women's Hospital. Cynthia Lemere, Ph.D., in the Selkoe group, and Ruth Maron, Ph.D., in the Weiner group, led the experiments. The findings are reported in the October 2000 issue of the Annals of Neurology . The National Institute on Aging (NIA) and the National Institute of Allergy and Infectious Disease (NIAID), both part of the Federal government's National Institutes of Health, supported the study.
This Annals report follows a 1999 report on an AD vaccine by scientists at Elan Pharmaceuticals. In Elan's research, injections of the beta amyloid peptide were shown to be effective in stopping the formation of plaques in the same strain of mice that were used in the Harvard study, mice that were specially engineered to develop AD-like plaques. The company is now in the early stages of testing regular injections of an experimental beta amyloid vaccine for its safety in humans.
This Harvard study delivered the beta-amyloid peptide nasally, using a method somewhat like the inhalers used to deliver allergy and asthma medicines. Scientists are interested in testing the delivery of the peptide nasally because it may be better tolerated in humans than repetitive injections over the long-term. In this study, the strength of antibodies resulting from nasal administration of the vaccine was not as great as that from the injection approach, although still significantly effective against plaque formation. The study also identified cellular immune responses in the brains of mice treated nasally with amyloid that may contribute to reducing plaque levels. Apart from the way the vaccine was administered and differences in the strength of the response, the latest study, in most other respects, is consistent with the Elan work, demonstrating that an immunological intervention—such as a vaccine—can lower plaque formation associated with AD.
"This whole area of research on Alzheimer's disease vaccines is extremely exciting," says D. Stephen Snyder, Ph.D., who heads the Etiology of AD program at NIA. "There is a long way to go—likely several years—before we have the answers to the question of whether there will be an effective and safe vaccine against AD. For now, though, we are very encouraged by this latest step." Further research in the general area of vaccines for AD is being solicited by NIA, which is expected in the coming months to publish a request for scientific proposals as part of an AD initiative announced in July by The White House.
"Although vaccines have long been a key public health tool for preventing communicable diseases caused by microbes," adds Elaine Collier, M.D., acting chief of NIAID's Clinical Immunology Branch, "using them to treat or prevent non-infectious diseases that have a strong immunology component is a new area of research. This study demonstrates the promise of this new approach." NIAID is developing similar approaches to prevent other chronic diseases, including autoimmune diseases, and is working to establish a network of investigators focused on this effort.
In the last few years, research has intensified into ways to prevent or lower the formation of plaques and tangles in the brain that are the major hallmarks of AD. These characteristics, along with inflammation and other pathological changes in the brain, cause damage that eventually can lead to dementia. Amyloid plaques occur when individual peptide fragments clipped from a larger protein, called the amyloid precursor protein, or APP, clump together in the brain. Scientists in both the public and the private sectors are trying to interfere with production of the protein fragment, beta amyloid, or inhibit its clumping into plaques. In a vaccine, some part of the beta amyloid peptide would be administered, at an age and in doses and routes yet to be determined, triggering an immune response against the offending peptide and possibly protecting against disease development. While the exact mechanisms behind the beta amyloid vaccine are not fully understood, researchers believe that the vaccine generates antibodies that bind to beta amyloid in the mouse brain and enhance its removal from the nervous system. The long-term effects of this vaccine on normal brain function need further study.
The Weiner and Selkoe teams studied 52 transgenic mice with plaques similar to those in human AD. The mice were divided into several groups -- those left untreated, those given oral or nasal myelin basic protein (MBP, a brain protein known to suppress a certain autoimmune disorder, but not AD), and mice treated orally or nasally with the beta-amyloid vaccine. The animals were treated for about 7 months, receiving weekly doses after a more intense regimen during the first week.
At the end of the study, only the brains of mice treated with the nasal beta amyloid vaccine showed a significant effect, in both the hippocampus and the temporal cortex, regions of the brain in which plaques of AD accumulate. In addition, biochemical analyses showed that beyond appearing to block the formation of plaques, the vaccinated mice had less beta amyloid content in whole brain tissue, a reduction of approximately 40 percent to 50 percent compared with the control mice. The vaccine appeared to lower the number of plaques that formed in the brain and, by doing so, to lower the amount of inflammatory changes in the brain associated with plaques.
The NIA and the NIAID are two of the 25 institutes and centers at the National Institutes of Health. NIA leads the federal effort to understand and eventually treat AD, conducting and supporting research like the Harvard study reported today. Also supports basic, clinical, epidemiological, and social research on aging and the special needs of older people and their families.
The NIA operates the Alzheimer's Disease Education and Referral Center (ADEAR), which provides information to health professionals and the public on AD and memory impairment. For more information, contact ADEAR at 1-800-438-4380, or through its website http://www.nia.nih.gov/Alzheimers/ .
NIAID supports basic and applied research to prevent, diagnose and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.