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An unusual collaboration involving MIT-affiliated scientists from three different branches of chemistry has produced the first concrete structural information on an amyloid plaque similar to that found in the brains of patients with Alzheimer's disease.
This information, reported in the November issue of Nature Structural Biology, represents an important step forward in understanding the biology of Alzheimer's disease and may some day lead to new diagnostic and treatment techniques.
Scientists from the MIT Department of Chemistry, the Francis Bitter Magnet Lab and the Whitehead Institute for Biomedical Research used revolutionary solid-state nuclear magnetic resonance (NMR) and computer modeling to determine the structure of a fragment of the beta-amyloid protein. In Alzheimer's patients, fibroid beta-amyloid plaques are common in the hippocampus (a part of the brain responsible for memory), although researchers have yet to determine how the plaques are related to the symptoms of the disease. The ultimate goal of current beta-amyloid research is to determine how the plaques form in the brain and, eventually, whether there might be some way of dissolving them.
Efforts to decipher the structure of beta-amyloid using conventional techniques have failed because the molecule is neither soluble nor crystalline. To overcome this problem, Associate Professor Peter T. Lansbury Jr., well known for his work in protein synthesis, recruited Professor Robert G. Griffin (director of the Francis Bitter Magnet Lab), and Bruce Tidor, then a Whitehead Fellow and currently assistant professor of chemistry at MIT.
The three laboratories focused on one particular fragment of the beta-amyloid protein. Previous studies by Dr. Lansbury had shown that this fragment, or peptide, forms thread-like structures (fibrils) similar to those formed by the full-length beta-amyloid protein, and thus could act as a model for understanding the development of the complete plaque.
Dr. Lansbury and his associates synthesized several different versions of the peptide, labeled them by inserting radioactive isotopes in place of individual carbon atoms, and then used them to grow fibrils. The next step involved Dr. Griffin's laboratory, which employed newly developed solid-state NMR technologies to measure the distances between the labeled atoms. After each set of measurements, Dr. Tidor's group used computer simulations and molecular modeling to evaluate the data and determine which new experiments would be most likely to narrow the field from many possible structures to one unique structure.
"Here is a unique collaboration of three groups that each look at things very differently. To examine the structure of this amyloid, we taught each other what was possible in each of our fields and this allowed us to develop a strategy to attack this problem," Dr. Tidor said.
The collaboration produced a new model system for studying the rules that govern the formation of beta-amyloid plaques. In the future, such knowledge could be used to design new proteins that bind to the plaques for diagnostic purposes, or molecules capable of disrupting or dissolving the plaques if they are found to play a major role in the pathogenesis of Alzheimer's disease.
This work was funded in part by the National Institutes of Health, the American Health Assistance Foundation, the Alzheimer's Association and the W.M. Keck Foundation.
A version of this article appeared in MIT Tech Talk on November 1, 1995.