Progress in FY2011 has been in the following areas: 1. AMYLOID FIBRIL STRUCTURES DERIVED FROM BRAIN TISSUE: We have developed a new protocol for partial purification of amyloid from brain tissue obtained at autopsy, and a new protocol for using this material as a """"""""seed"""""""" for growing fibrils from synthetic, isotopically-labeled peptide. With the new protocols, 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 diseased Alzheimer's disease patient, we find that there is a single fibril structure in this tissue, a surprising result. We have performed numerous solid state NMR measurements on these brain-seeded fibrils, with isotopic labeling at specific sites and with uniform isotopic labeling. We now have a full set of structural constraints that will lead to a specific structural model in FY2012. 2. SURPRISING 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 FY2011, we have developed 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.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$477,140
Indirect Cost
City
State
Country
Zip Code
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
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 (2015) Amyloid polymorphism: structural basis and neurobiological relevance. Neuron 86:632-45
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
McDonald, Michele; Box, Hayden; Bian, Wen et al. (2012) Fiber diffraction data indicate a hollow core for the Alzheimer's a? 3-fold symmetric fibril. J Mol Biol 423:454-61

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