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2006 Grant - Meredith
Structure of Mutant Beta-Amyloid Fibrils Examined by Solid-State NMR
Stephen C. Meredith, M.D., Ph.D.
University of Chicago
2006 Investigator-Initiated Research Grant
Beta-amyloid is a protein fragment that may be a key factor in damaging cell-to-cell communication and causing the loss of brain cells in Alzheimer's disease. Beta-amyloid is chemically "sticky"-it tends to join with other beta-amyloid fragments. Clusters of beta-amyloid fragments eventually form long chains called fibrils, which, in turn, form larger structures that eventually form amyloid plaques.
Studies have shown that people with the rare inherited form of Alzheimer's disease appear to have beta-amyloid molecules with distinct structural differences from the "normal" beta-amyloid molecules found in the brains of people with the more common noninherited, late-onset Alzheimer's. The "mutated" beta-amyloid not only forms plaques in the brain tissue but also leads to significant beta-amyloid deposits in the blood vessels of the brain.
Stephen C. Meredith, M.D., Ph.D., and colleagues have observed that the structural differences in mutated beta-amyloid appears to alter the assembly and ultimate structure of fibrils. These differences may result in slightly different functional properties of fibrils in inherited and noninherited forms of the disease and subsequently different pathological mechanisms.
Dr. Meredith's team has hypothesized that normal beta-amyloid preferentially adopts a structure that leads to plaques and that mutated beta-amyloid prefer-entially adopts a structure that leads to vascular deposits. The investigators will use high-resolution imaging technology to exam and characterize the structural properties of fibrils from normal and mutated beta-amyloid. The outcome of this work may help elucidate differences in pathology and disease manifestation.