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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The paper on this research, BIOT 421, will be presented at 2:05 p.m., Thursday, March 17, at the Convention Center, Room 31A, during the "Tissue Engineering/Biomaterials" symposium.
Theresa Good, Ph.D., is a chemist with The University of Maryland-Baltimore County in Maryland. She is an associate professor in the school's Department of Chemical and Biochemical Engineering.
BIOT 421 Development of biomimetic materials for Alzheimer's disease
Dhara Patel, Chemical Engineering, Texas A&M Univeristy, and Theresa Good, Chemical and Biochemical Engineering, UMBC
Beta-amyloid peptide is the primary protein component of senile plaques in Alzheimer's disease and is believed to be associated with neurotoxicity in the disease. We have shown that beta amyloid binds with relatively high affinity to clustered sialic acid residues on cell surfaces and propose that artificial sialic acid clusters conjugated to dendritic polymers can compete with clustered sialic acid residues on cell surface gangliosides for beta amyloid binding. In the current work, we examine the relationship between dendrimer size, charge, degree of sialic acid modification, and sialic acid conjugation chemistry on the ability of these dendritic polymers to bind beta amyloid, prevent beta amyloid toxicity, and serve as recognition surfaces in surface modified spectroscopic assays for beta amyloid. This work may lead to the development of new tools and/or therapeutics for use in Alzheimer's disease.
Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public)
Alzheimer's disease (AD) is a neurodegenerative disorder that impairs memory, thinking and leads ultimately to death in approximately 8 years after onset. An astonishing 4.5 million Americans were estimated to have Alzheimer's disease in 2003 and the number is predicted to reach anywhere from 11.3 to 16 million by 2050. There are two problems of this disease that we are trying to address: 1)the development of a therapeutic that targets one of the probable cause of the disease, and 2)the development of a means of detecting the onset of disease. As of today, there is no cure for the disease. The drugs available in the market today merely suppress the symptoms of the disease, but do not affect the cause of the disease. In addition, to date, there is no definite way of diagnosing the disease prior to death. Diagnosis of probable Alzheimer's is made based on memory tests premortum. The only way to positively know that a person has Alzheimer's disease is post-mortem analysis of the brain. One of the hallmarks of Alzheimer's brains is the accumulation of a protein called beta-amyloid, which in some aggregated structural states, is believed to kill neurons. It has been shown that this toxic protein binds to cells via the cell-surface sialic acid containing molecules called gangliosides. In the current work, we have developed sialic acid conjugated star shaped polymers that mimic cell-surface gangliosides, and show by in-vitro experiments that these biomimetic polymer molecules attenuate the toxic effects of beta-amyloid. We've examined the relationship between different properties of these biomimetic molecules on their ability to bind beta amyloid, prevent beta amyloid toxicity, and serve as recognition surfaces in assays for beta amyloid that might be useful in diagnosis of Alzheimer's disease. The types of biomimetic molecules we are developing represent a novel approach in Alzheimer's research. This work may lead to the development of new tools and/or therapeutics for use in Alzheimer's disease.
How new is this work and how does it differ from that of others who may be doing similar research?
So far, no one has tried to use sialic acid conjugated polymers to compete with cell surface sialic acid for beta-amyloid binding. ofcourse there is a long way to go before one can inject these molecules into 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.
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