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2008 Grants - Ishii
Toxicity and Structure of Aggregated Alzheimer's Beta-Amyloid
Yoshitaka Ishii, Ph.D.
University of Illinois - Chicago
2008 Investigator-Initiated Research Grant
The protein fragment beta-amyloid is a key suspect in Alzheimer's disease. This fragment tends to accumulate into long chains called fibrils. The fibrils, in turn, become the main component of amyloid plaques, deposits that accumulate among brain cells and are one of the hallmarks of Alzheimer's. However, beta-amyloid is a naturally accruing substance in the brain, and not all forms of the protein fragment are equally toxic. The most toxic known beta-amyoid type, called beta-amyloid (1-42), has a particular arrangement of building blocks known as amino acids. Furthermore, recent studies have found that smaller accumulations of beta-amyloid, which are formed early in the Alzheimer process, may be more toxic than amyloid fibrils or plaques.
For this proposed study, Yoshitaka Ishii, Ph.D., and colleagues will analyze three toxic forms of beta-amyloid. For this effort, they will use a sophisticated imaging technique called solid-state nuclear magnetic resonance imaging. Dr. Ishii's team will first identify the precise structure of beta-amyloid (1-42) fibrils. Such fibrils have proven difficult to examine accurately in earlier studies. Second, the researchers will analyze beta-amyloid (1-42) fibrils to which copper ions have been bound. They hope to verify previous research indicating that copper-bound amyloid fibrils produce hydroxyl peroxide, a substance toxic to brain cells. Finally, the researchers will conduct analyses of small aggregates of beta-amyloid (1-42). Using cultured nerve cells, they will compare the toxicity of these aggregates to that of amyloid fibrils.
Results of Dr. Ishii's research should shed new light on the biological mechanisms underlying beta-amyloid toxicity in Alzheimer's. Ultimately, such knowledge could lead to more precise treatments for the disease.