Early Divergence in Misfolding Pathways of Amyloid-Beta Peptides |
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Authors: | Dr. Salvatore Mamone Dr. Stefan Glöggler Dr. Stefan Becker Dr. Nasrollah Rezaei-Ghaleh |
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Affiliation: | 1. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Von-Siebold-Str. 3A, 37075 Göttingen, Germany;2. Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany |
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Abstract: | The amyloid cascade hypothesis proposes that amyloid-beta (Aβ) aggregation is the initial triggering event in Alzheimer's disease. Here, we utilize NMR spectroscopy and monitor the structural dynamics of two variants of Aβ, Aβ40 and Aβ42, as a function of temperature. Despite having identical amino acid sequence except for the two additional C-terminal residues, Aβ42 has higher aggregation propensity than Aβ40. As revealed by the NMR data on dynamics, including backbone chemical shifts, intra-methyl cross-correlated relaxation rates and glycine-based singlet-states, the C-terminal region of Aβ, especially the G33-L34-M35 segment, plays a particular role in the early steps of temperature-induced Aβ aggregation. In Aβ42, the distinct dynamical behaviour of C-terminal residues at higher temperatures is accompanied with marked changes in the backbone dynamics of residues V24-K28. The distinctive role of the C-terminal region of Aβ42 in the initiation of aggregation defines a target for the rational design of Aβ42 aggregation inhibitors. |
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Keywords: | amyloid beta-peptides NMR spectroscopy singlet-state aggregation Alzheimer's disease |
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