Apr. 11, 2005 SAN DIEGO, March 17 — 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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