Progress in FY2018 has been in the following areas: (1) MOLECULAR STRUCTURE OF AMYLOID-BETA FIBRILS DERIVED FROM HUMAN BRAIN TISSUE: In previous experiments (Qiang et al., Nature 2017), we used solid state NMR spectra to identify the most common 40-residue and 42-residue amyloid-beta fibril polymorphs in cortical tissue from Alzheimer's disease (AD) patients. We found a single predominant polymorph of 40-residue amyloid-beta (Ab40) fibrils in typical long-duration AD patients and posterior cortical atrophy AD patients, and two predominant polymorphs of 42-residue amyloid-beta (Ab42) fibrils. We are now developing full molecular structural models for these predominant polymorphs, beginning with the Ab40 polymorph. We have obtained and published full solid state NMR chemical shift assignments (Ghosh et al., Chem. Comm. 2018) and are now acquiring spectra to identify inter-residue contacts that will be used to develop a structural model. We are also attempting to use cryoEM images to develop 3D density models for these fibrils. (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. This work has now been published (Yau and Tycko, Prot. Sci. 2018). We are now planning experiments with transgenic mouse models of Alzheimer's disease, to test whether injection of fibril-seeded polyacrylamide hydrogel microspheres into lateral ventricles of the brain prevents or delays formation of amyloid-beta plaques in the mouse brain tissue.
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