387273 Solid State NMR Evidence for Antiparallel β-Sheet Structure within Toxic Oligomers of the Alzheimer's β-Amyloid Peptide

Thursday, November 20, 2014: 9:24 AM
205 (Hilton Atlanta)
Danting Huang1,2, Maxwell Zimmerman1,2, Patricia K. Martin3, A. Jeremy Nix3, Terrone L. Rosenberry3 and Anant K. Paravastu1,2, (1)Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, FL, (2)National High Magnetic Field Laboratory, Tallahassee, FL, (3)Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL

Pathological and biochemical evidence links Alzheimer’s Disease more closely to soluble aggregates (oligomers) of the β-amyloid peptide (Aβ) rather than more stable amyloid fibrils. We are interested in understanding the molecular structural differences between oligomers and fibrils and underlying self-assembly pathways.  We have previously reported a procedure for production of stable homogeneous oligomers of Aβ42 (the 42-residue variant), in the presence of sodium dodecylsulfate (SDS) micelles, which is compatible with solid state nuclear magnetic resonance (NMR) structural characterization.  We will present new NMR data which indicate that oligomers differ from fibrils in terms of β-strand organization into β-sheets, suggesting that oligomers and fibrils are formed along distinct self-assembly pathways. In particular, two-dimensional 13C-13C exchange experiments on oligomers reveal that the Aβ42 molecules are organized into anti-parallel β-sheets and indicate a specific inter-strand arrangement. We will discuss these new structural constraints in terms of previously proposed Aβ oligomeric and fibrillar structural models.  In addition, we will present new candidate full-atom molecular models for Aβ42 oligomers, established using experimentally constrained molecular simulations.

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See more of this Session: Fundamentals of Protein Folding in Diseases
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division