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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Yau, Wai-ming Qiang, Wei Mattson, Mark P. Luo, Yongquan Tycko, Robert |
| Description | Author Affiliation: Qiang W ( Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.); |
| Abstract | Wild-type, full-length (40- and 42-residue) amyloid ß-peptide (Aß) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-ß structures in which the ß-sheets have an in-register parallel supramolecular organization. In contrast, recent studies of fibrils formed in vitro by the Asp23-to-Asn mutant of 40-residue Aß (D23N-Aß(1-40)), which is associated with early onset neurodegeneration, indicate that D23N-Aß(1-40) fibrils can contain either parallel or antiparallel ß-sheets. We report a protocol for producing structurally pure antiparallel D23N-Aß(1-40) fibril samples and a series of solid state nuclear magnetic resonance and electron microscopy measurements that lead to a specific model for the antiparallel D23N-Aß(1-40) fibril structure. This model reveals how both parallel and antiparallel cross-ß structures can be constructed from similar peptide monomer conformations and stabilized by similar sets of interactions, primarily hydrophobic in nature. We find that antiparallel D23N-Aß(1-40) fibrils are thermodynamically metastable with respect to conversion to parallel structures, propagate less efficiently than parallel fibrils in seeded fibril growth, and therefore must nucleate more efficiently than parallel fibrils in order to be observable. Experiments in neuronal cell cultures indicate that both antiparallel and parallel D23N-Aß(1-40) fibrils are cytotoxic. Thus, our antiparallel D23N-Aß(1-40) fibril model represents a specific 'toxic intermediate' in the aggregation process of a disease-associated Aß mutant. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 12 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Amyloid Beta-Peptides Chemistry Amyloid Peptide Fragments Alzheimer Disease Metabolism Binding, Competitive Magnetic Resonance Spectroscopy Microscopy, Electron Microscopy, Electron, Transmission Models, Biological Models, Molecular Molecular Conformation Mutation Neurodegenerative Diseases Thermodynamics Research Support, N.I.H., Intramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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