The aggregation and deposition of the Abeta peptide as amyloid plaques is a key event associated with the neurodegeneration in Alzheimer's disease (AD). As one of the few research groups that has successfully studied the Abeta peptide in solution using high-resolution NMR methods, a major focus of our.research is to unravel the chemical mechanisms associated with amyloid formation. The NMR approach is extremely powerful for studying proteins, in that it can detect site-specific aspects of the structures and dynamics in solution at the atomic level. In this application, we will determine the structures of early-folded Abeta aggregates, including the Abeta-derived diffusible ligands (ADDLs). Current thinking is that these soluble beta-sheet aggregates, and not the insoluble amyloid plaques, are the real culprits responsible for AD-associated neuronal death. Detailed information of the intermolecular organization within the ADDL assembly remains unknown. Our preliminary data demonstrate that NMR studies of ADDLs and other early folded beta-structures are feasible. We hypothesize that the ADDL assemblies have micelle-like properties, in which the Abeta hydrophobic C- terminus becomes clustered around the center of a micelle-like structure. Related goals will disentangle the effects of the Met35 side chain oxidation state and Abeta aggregation/amyloid formation. Although Met35ox is found in variable amounts in postmortem amyloid plaques, the chemistry and biological role of these oxidative events remains unknown. This work will provide a solid chemical foundation for the relationship between the Met35 oxidative state and the oxidative stress events associated with AD, such as whether or not the longer Abeta(1-42) may be more reactive toward reactive oxidative species (ROS) in vivo. Relevance to Public Health: Knowledge of the chemical mechanisms of Abeta aggregation, combined with our unique use of NMR, will provide critical atomic level details that will eventually lead to better therapeutic approaches to prevent amyloid formation in AD.
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