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. Alzheimer's 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)40 fibril. 2. Characterize the development of structure and neurotoxicity in prefibrillar intermediate forms of A(beta)40. Contrary to the impression one might derive from recently published literature, the molecular structure of amyloid fibrils that accumulate in Alzheimer's disease has not been fully elucidated. For several reasons, amyloid fibrils are ideally suitable for the application of 2D-IR to the determination of protein structure. First the fibrils are composed of polypeptide strands of 40 residues that are readily synthesized with site-specific isotopic labels. Second, polypeptides within a fibril assume extremely regular secondary structure. This helps and simplifies our interpretation of 2D-IR spectra. Third, beta-sheets are likely to exhibit more intense and even better defined peaks than alpha-helices because the amide transition dipoles in a beta-sheet are more favorably aligned than they are in an alpha-helix. Also, labels in a parallel beta-sheet are strongly coupled when 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.