Progress in FY2012 has been in the following areas: 1. AMYLOID FIBRIL STRUCTURES DERIVED FROM BRAIN TISSUE: We have previously developed a protocol for partial purification of amyloid from brain tissue obtained at autopsy, and for using this material as a """"""""seed"""""""" for growing fibrils from synthetic, isotopically-labeled peptide. With this protocol, we can create 1 mg fibril samples suitable for solid state NMR and electron microscopy studies, starting with 1 g of brain tissue, in a single fibril growth step. Applying this protocol to fronto-temporal lobe and occipital lobe tissue from a Alzheimer's disease patient, we found that there is a single fibril structure in this tissue, a surprising result. We have performed numerous solid state NMR measurements and electron microscopy measurements on these brain-seeded fibrils, with isotopic labeling at specific sites and with uniform isotopic labeling. From these data, we have developed a full structural model for brain-derived fibrils, the first of its kind. The brain-derived fibrils are structurally similar to fibrils that we have created synthetically and characterized in previous years, but have some unique features (e.g., the entire 40-residue peptide sequence is structurally ordered). We have also found that other Alzheimer's disease patients have different fibril structures in their brain tissue, reflected in significant differences in NMR chemical shifts in our measurements and somewhat different morphologies in electron microscopy images. These results are being written up for publication in FY2013. 2. ANTIPARALLEL BETA-SHEET STRUCTURE IN MUTANT BETA-AMYLOID FIBRILS: In collaboration with S.C. Meredith, we have recently shown that the Asp23-to-Asn mutant of human beta-amyloid (D23N mutant, or Iowa mutant) is capable of forming amyloid fibrils that contain antiparallel beta-sheets. This is the first demonstration that a full-length peptide or protein could form fibrils that contain antiparallel (rather than parallel) beta-sheets. In FY2012, we completed and published a full molecular structural model for antiparallel D23N-Abeta fibrils, revealing how similar sets of hydrophobic interactions can stabilize either parallel or antiparallel structures. In collaboration with Mattson's group in NIA, we have shown that both parallel and antiparallel structures are neurotoxic in cell cultures. We have shown that antiparallel structures are metastable with respect to eventual conversion to parallel structures. 3. CORRELATIONS BETWEEN FIBRIL STRUCTURE AND DISEASE PROGRESSION: Using the protocols described in #1, we have begun investigating possible correlations between beta-amyloid fibril structure (as revealed by solid state NMR and electron microscopy) and clinical history/pathology. For these experiments, we have established a collaboration with Prof. John Collinge of University College London, whose group has provided us with a set of brain tissue samples from AD patients with distinct histories. Preliminary data, obtained in the past several months, suggest that correlations do exist, which in turn suggests that the details of amyloid fibril structure may influence disease progression. These experiments will continue in FY2013.

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Yau, Wai-Ming; Tycko, Robert (2018) Depletion of amyloid-? peptides from solution by sequestration within fibril-seeded hydrogels. Protein Sci 27:1218-1230
Qiang, Wei; Yau, Wai-Ming; Lu, Jun-Xia et al. (2017) Structural variation in amyloid-? fibrils from Alzheimer's disease clinical subtypes. Nature 541:217-221
Tycko, Robert (2016) Molecular Structure of Aggregated Amyloid-?: Insights from Solid-State Nuclear Magnetic Resonance. Cold Spring Harb Perspect Med 6:
Tycko, Robert (2016) Alzheimer's disease: Structure of aggregates revealed. Nature 537:492-493
Tycko, Robert (2015) Amyloid polymorphism: structural basis and neurobiological relevance. Neuron 86:632-45
Potapov, Alexey; Yau, Wai-Ming; Ghirlando, Rodolfo et al. (2015) Successive Stages of Amyloid-? Self-Assembly Characterized by Solid-State Nuclear Magnetic Resonance with Dynamic Nuclear Polarization. J Am Chem Soc 137:8294-307
Tycko, Robert (2014) Physical and structural basis for polymorphism in amyloid fibrils. Protein Sci 23:1528-39
Lu, Jun-Xia; Qiang, Wei; Yau, Wai-Ming et al. (2013) Molecular structure of ?-amyloid fibrils in Alzheimer's disease brain tissue. Cell 154:1257-68
Qiang, Wei; Kelley, Kevin; Tycko, Robert (2013) Polymorph-specific kinetics and thermodynamics of ?-amyloid fibril growth. J Am Chem Soc 135:6860-71
Qiang, Wei; Yau, Wai-Ming; Luo, Yongquan et al. (2012) Antiparallel ?-sheet architecture in Iowa-mutant ?-amyloid fibrils. Proc Natl Acad Sci U S A 109:4443-8

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