Progress in FY2017 has been in the following areas: (1) AMYLOID FIBRIL STRUCTURES DERIVED FROM BRAIN TISSUE: We published the results of studies in which molecular structures of 40-residue and 42-residue amyloid-beta fibrils that develop in brain tissue of Alzheimer's disease patients were characterized by solid state NMR and electron microscopy. In these studies, we find one predominant 40-residue amyloid-beta fibril polymorph, and two predominant 42-residue fibril polymorphs. In tissue from patients with rapidly developing Alzheimer's disease, molecular structures of 40-residue fibrils have significantly greater heterogeneity. The NMR signatures of these predominant polymorphs differ from those of fibrils whose structures have been determined previously. (2) ADSORPTION OF AMYLOID-BETA PEPTIDES INTO SEEDED GELS: AD is generally believed to result from aggregation of amyloid-beta peptides in brain tissue. Amyloid-beta aggregation depends on supersaturation, i.e., on the development of amyloid-beta concentrations that exceed equilibrium solubility levels in the tissue. We have shown that amyloid-beta concentrations in solutions can be reduced to their solubility levels by addition of hydrogels that contain fibril seeds (i.e., short fragments of fibrils). This process involves diffusion of soluble peptide molecules into the gels and subsequent addition to the growing ends of the fibril seeds. Experiments have been performed successfully on simply phosphate buffer solutions at 24 C and on solutions in fetal bovine serum at 37 C. A publication describing these experiments is in preparation.
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