Progress in FY2013 has been in the following areas: AMYLOID FIBRIL STRUCTURES DERIVED FROM BRAIN TISSUE: We have published the first experimentally-based, detailed molecular structural model for beta-amyloid fibrils that actually developed in the brain tissue of an Alzheimer's disease (AD) patient. The same publication included solid state NMR and electron microscopy data for a second patient, showing that two different patients can develop structurally distinct beta-amyloid fibrils in their brains (although the structure within a given patient was highly homogeneous). The two patients had different clinical histories, with the first patient receiving an initial diagnosis of Lewy body dementia and the second patient receiving an initial diagnosis of AD. In collaboration with Prof. John Collinge of University College London, we have now obtained solid state NMR and electron microscopy data for fibrils derived from 30 brain tissue samples from autopsies of AD patients in three categories (typical long history, posterior cortical atrophy, short duration). Using our published amyloid extraction and seeding protocols, isotopically labeled fibrils were prepared using both 40-residue and 42-residue beta-amyloid peptides. The solid state NMR data suggest that most AD patients develop the same predominant 40-residue fibril structure in their brains, but that short duration patients can develop different and more heterogeneous structures. Results for 42-residue fibrils are still under analysis. These experiments are aimed at determining whether structural variations in beta-amyloid fibrils correlate with variations in AD development. If such correlations are found to be significant, then it may become important to develop imaging agents that distinguish among different fibril structures, and possibly to develop beta-amyloid aggregation inhibitors that have structural specificity.

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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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