2D IR OF AMYLOID PEPTIDES AND FIBRIL GROWTH

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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. Alzheimers disease and several other prevalent neurodegenerative diseases are characterized by the misfolding and aggregation of proteins into fibrils composed of parallel beta-sheets. Either the fibrillar proteins or prefibrillar oligomeric intermediate forms appear to have neurotoxic properties that result in neuronal degeneration and death. There are significant discrepancies between recently proposed structures for the A-beta fibril, and little is known about the structure of prefibrillar intermediate forms of A-beta. It is clear that new approaches and new kinds of data are needed. A better understanding of how these pathological structures form is key to understanding why they form, and to developing therapeutic interventions for these diseases. Therefore, we aim to 1. Test, verify, or refine structural models of the mature A-beta fibril. 2. Characterize the development of structure and neurotoxicity in prefibrillar intermediate forms of A-beta. Contrary to the impression one might derive from recently published literature, the molecular structure of amyloid fibrils that accumulate in Alzheimers disease has not been solved. For several reasons, amyloid fibrils are an ideal sample for the application of 2D-IR-COSY to the determination of protein structure. First, fibrils are composed of polypeptides that are readily synthesized with site-specific isotopic labels. Second, polypeptides within a fibril are known to assume extremely regular secondary structure. This aids and simplifies our interpretation of 2D-IR-COSY spectra. Third, beta-sheets are likely to exhibit more intense and even better defined peaks than alpha-helices because transition dipoles in a beta-sheet are better aligned to each other than they are in an alpha-helix. Also, labels in a parallel beta-sheet are coupled to each other because they are aligned if the strands of the sheet are in register. This gives rise to inter-strand coupling that would not occur in an alpha-helix. Fourth, amyloid represents a pathological material whose structure is of tremendous biomedical interest.