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2008 Grants - Nilsson
Probing Amyloid-Beta Structure and Aggregation with Nonnatural Amino Acids
Bradley L. Nilsson, Ph.D.
University of Rochester
Rochester, New York
2008 New Investigator Research Grant
Beta-amyloid is a protein fragment that aggregates into several forms that are toxic to neurons. Small, soluble clusters of beta-amyloid (oligomers) and large, insoluble aggregates (amyloid fibrils or amyloid plaques) are all associated with Alzheimer's disease. Beta-amyloid itself can fold into a variety of different conformations, some of which are more susceptible to aggregation into oligomers or fibrils. Hence, the principles that govern the folding of beta-amyloid are important for researchers attempting to understand the causes of disease and to develop effective treatments.
Bradley L. Nilsson, Ph.D., and colleagues are studying how beta-amyloid folds and how that folding affects its aggregation and toxicity. To perform these studies, the researchers have constructed beta-amyloid molecules that are altered by substituting unnatural amino acids for natural amino acids. (Amino acids are the chemical building blocks of all proteins.) By inserting unnatural amino acids into known amino-acid positions in the beta-amyloid molecule, the researchers can infer the normal role of the "eliminated" amino acid from the folding of the altered protein fragment.
Dr. Nilsson and colleagues also will utilize another tool, known as a photo-switchable turn mimic, for studying the folded structure of beta-amyloid. This tool enables them to control the folding of the molecule at specific locations. These experiments may improve our understanding of the forces leading to formation of toxic forms of beta-amyloid. They may also provide insights into mechanisms that prevent the formation of such molecules, potentially leading to the development of treatments for Alzheimer's disease.