Chemical decoy shows
promise
for slowing Alzheimer’s
Newswise — A chemical decoy that shows promise in blocking the toxic
brain proteins thought to cause Alzheimer’s disease was described
here today at the 229th national meeting of the American Chemical
Society, the world’s largest scientific society.
The decoy, which has only been tested in cell culture, is a polymer
developed by a team of chemists at The University of
Maryland-Baltimore County and Texas A&M University.
If successful in future studies, it could lead to new, more effective
drugs for treating the disease, they say.
The polymer also holds potential
as a marker for diagnosing the disease in live subjects, according
to the researchers. Currently, the disease is definitively diagnosed
only upon autopsy.
“This is the first time anyone has
tried this novel approach using a biomimetic polymer to fight
Alzheimer’s,” says study leader Theresa Good, Ph.D., a chemist with
the University of Maryland-Baltimore County. Unlike most current
drugs designed to treat Alzheimer’s, this compound attempts to
target one of the underlying causes of the disease rather than just
the symptoms. “Of course, there is a long way to go before one can
use these molecules in the human body, but so far, in vitro studies
look promising, not only from a therapeutic point of view, but also
from a diagnostics one.”
Alzheimer’s is a chronic,
incurable form of dementia that primarily strikes the elderly and
causes severe memory loss and eventually, death. A complex disease
with many probable causes, it is most often characterized by the
presence of senile plaques and tangles in the brain, which are seen
upon autopsy.
These senile plaques contain beta
amyloid protein, a protein that is formed in the brain and other
cells throughout the body but, for reasons that are not entirely
clear, seems to accumulate in the brain of Alzheimer’s victims
rather than elsewhere in the body. Researchers believe there are
many different forms of beta amyloid circulating through the
bloodstream, but only certain species are thought to be toxic. It is
the diffusible beta amyloid species — tiny proteins that can easily
reach the brain — that are thought to be toxic in Alzheimer’s and
associated with brain cell death and neurodegeneration.
In the current study, Good and her
associates found evidence that beta amyloid preferentially binds to
sialic acids, naturally occurring sugars that have increasingly been
shown to be involved in many cell activities, including signaling
and differentiation. Sialic acids are particularly abundant on the
surfaces of brain cells but also found in lower amounts in the rest
of the body. The researchers theorized that creating a polymer that
acts like the surface of a brain cell, with its abundance of sialic
acids, could lure toxic beta amyloid out of circulation and prevent
its accumulation and binding to actual brain cells. If beta amyloid
doesn’t bind to the brain cells, most scientists believe that it
won’t be able to kill the brain cells, the researchers say.
Good’s group then designed a group
of synthetic, star-shaped polymers with surface sialic acids to
mimic the molecules found on brain cell surfaces. Using a human
neuron-derived cell line, the researchers showed in test tube
studies that addition of the polymer serves as an effective “decoy”
for attracting the circulating beta amyloid proteins away from the
neuron-like cells. The resulting polymer-amyloid complex can then be
broken down and removed by specialized cells in the brain, the
researcher theorizes.
Because the decoy molecules look
like components of normal human brain cells, they will hopefully be
less likely to cause side effects, which have plagued many promising
Alzheimer’s drug candidates, Good says. She notes, for instance,
that experimental vaccines targeting beta amyloid proteins have been
tried in animals, but these have triggered severe immune responses
that have prevented their use.
“We are currently trying to make
decoys with higher affinity and specificity for beta amyloid by
modifying the chemistry. Eventually we think we’ll be able to make
better decoys using molecular design,” Good says. Down the line, if
the polymers show promise in human studies, they could be developed
into injectable drugs or even pills to slow the progress of the
disease, she says.
The likely candidates for such
drugs would be people who have not yet developed signs of the
disease but who may be at increased risk, Good predicts. Candidates
would probably have to take the polymer drugs daily for the rest of
their lives to keep the disease at bay and minimize its damaging
effects, she says, adding that the approach is not a cure.
At present, there is no definite
way to diagnose Alzheimer’s disease prior to death; only a diagnosis
of probable Alzheimer’s, which is based on memory tests in suspected
candidates. Having a polymer marker that can pinpoint beta amyloid
levels could lead to a test that could diagnose Alzheimer’s in
living people, Good says.
The National Institutes of Health
funded this study. In addition to Good, other researchers in this
study include Dhara Patel, also of the University of
Maryland-Baltimore County, and James E. Henry, of Texas A&M
University in College Station, Texas.
The American Chemical Society is a
nonprofit organization, chartered by the U.S. Congress, with a
multidisciplinary membership of more than 159,000 chemists and
chemical engineers. It publishes numerous scientific journals and
databases, convenes major research conferences and provides
educational, science policy and career programs in chemistry. Its
main offices are in Washington, D.C., and Columbus, Ohio.
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