Interaction between amyloid beta peptide and an aggregation blocker peptide mimicking islet amyloid polypeptide |
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Authors: | Rezaei-Ghaleh Nasrollah Andreetto Erika Yan Li-Mei Kapurniotu Aphrodite Zweckstetter Markus |
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Institution: | 1. Department for NMR-based Structural Biology, Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.; 2. Division of Peptide Biochemistry, Technische Universität München, Freising, Germany.; 3. DFG Research Center for the Molecular Physiology of the Brain (CMPB), Göttingen, Germany.;University of Medicine and Dentistry of New Jersey, United States of America |
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Abstract: | Assembly of amyloid-beta peptide (Aβ) into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in Alzheimer's disease (AD) and interfering with Aβ aggregation is an important strategy in the development of novel therapeutic approaches. Prior studies have shown that the double N-methylated analogue of islet amyloid polypeptide (IAPP) IAPP-GI, which is a conformationally constrained IAPP analogue mimicking a non-amyloidogenic IAPP conformation, is capable of blocking cytotoxic self-assembly of Aβ. Here we investigate the interaction of IAPP-GI with Aβ40 and Aβ42 using NMR spectroscopy. The most pronounced NMR chemical shift changes were observed for residues 13-20, while residues 7-9, 15-16 as well as the C-terminal half of Aβ--that is both regions of the Aβ sequence that are converted into β-strands in amyloid fibrils--were less accessible to solvent in the presence of IAPP-GI. At the same time, interaction of IAPP-GI with Aβ resulted in a concentration-dependent co-aggregation of Aβ and IAPP-GI that was enhanced for the more aggregation prone Aβ42 peptide. On the basis of the reduced toxicity of the Aβ peptide in the presence of IAPP-GI, our data are consistent with the suggestion that IAPP-GI redirects Aβ into nontoxic "off-pathway" aggregates. |
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