Stultz leads effort to elucidate Alzheimer's protein structures

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August 22, 2008

Collin M. Stultz, the W.M. Keck Associate Professor of Biomedical Engineering in the Department of Electrical Engineering and Computer Science at MIT and principal investigator at the Research Laboratory of Electronics, RLE, has reported in the Aug. 22 issue of PLoS, the Public Library of Science Computational Biology, the development of a new computer-based technique to reveal the complex structure of proteins involved in Alzheimer's disease. This kind of understanding builds an important step toward the creation of new drugs that could prevent such protein structures from forming in the first place.

As reported by the MIT News Office, Aug. 21, Alzheimer's disease, the most common form of dementia affecting some five million Americans today, will reach 13.2 million by 2050. Stultz, who is also affiliated with the Harvard-MIT Division of Health Sciences and Technology, HST, reported that existing therapies are ineffective in slowing the rate of neurodegeneration in Alzheimer's patients, pointing to the urgent need to develop new treatments for Alzheimer's dementia.

As both an engineer and a practicing cardiologist (with appointments at Brigham and Women's Hospital and the West Roxbury Veteran's Administration Hospital), Stultz has approached the Alzheimer's problem using the results of biochemical studies to inform a novel computer modeling technique aimed at better understanding one of the two types of protein associated with the disease.

Tau protein molecules are peculiarly 'floppy' or unfolded so that in solution, they take on many different structures or forms, making it difficult to measure and characterize them. This situation contributes to the difficulty of studying the specific kinds of tau that are associated with Alzheimer's (not all tau proteins are harmful).

Stultz and HST graduate student Austin Huang engineered an approach they call Energy-minima Mapping and Weighting (EMW), in which a computer is fed large numbers of structures for both normal and mutant forms of tau (those associated with increased risk for Alzheimer's). When the data sets were compared, one struture was found to be common to the mutant form--and therefore likely to play a role in the pathologic process. That protein structure could then be used in the generation of new drugs.

So far, Stultz has focused on one tau mutant, but notes that there are several others on which he hopes to use the EMW method to create a list of all types of suspect conformations for known tau mutants. Drugs can then be designed for each.

This work was sponsored by a Jonathan Allen Junior Faculty Award.