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 propose to use x-ray absorption spectroscopy to characterize heavy metal sites (Zn(II) and Cu(II)) involved in the formation of amyloid fibrils. Zn(II) and Cu(II) have emerged as important factors in aggregation of amyloid beta (A?) peptide and the neurotoxicity of this process. We propose to investigate the local structure of Zn(II) and Cu(II) binding to fibrils formed with a number of truncated A? peptides in vitro. Of particular interest is the relationship between local metal coordination and aggregate morphology. It has also been shown that assembly of A? peptide is a nucleation-dependent process, which would allow us to follow the process over time, by flash-freeze techniques and/or physical separation, from aggregate nucleation through propagation of fibril formation.
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