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 about Alzheimer's
disease, contact ADEAR at 1-800-438-4380, or through its website at
www.alzheimers.org.
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.
