STRUCTURE AND REDOX CHEMISTRY OF TRUNCATED AMYLOID AGGREGATES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have been exploring the behaviour of amyloid-beta (Ab) and several truncated forms of the protein (Ab1-16, Ab1-38, Ab1-42) in the presence of redox-active transition metal ions (Fe, Cu) to explore the relationship between metals redox chemistry and Ab aggregation. Although this problem is being addressed in many different way our approach has focused on the role of methionine oxidation as a trigger for protein misfolding and subsequent aggregation. We have recently obtained the first STXM images at the S K-edge (as well as the Cu and Fe L-edges) of mouse brains to explore the relationship between physiological changes in brain tissue and whether these can be related to specific changes observed in vitro. The role of amyloid-beta aggregation in the progression of Alzheimers? disease has received significant attention. Although several possible mechanisms of aggregation have been postulated, the specifics have yet to be elucidated. One of the postulated mechanisms for protein aggregation in vivo posits that oxidation of the sole methionine in Ab begins a cascade of events, which eventually results in Ab aggregation. This redox trigger mechanism would involve Met oxidation from binding of redox-active transition metals to the membrane protein. We have been exploring this postulated mechanism using a wide range of techniques, focusing much of our effort on determining whether a correlation between methionine oxidation and transition metal (specifically Cu(II) and/or Fe(III)) reduction can be determined both in vitro and in vivo.