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Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides
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 a...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596873/ https://www.ncbi.nlm.nih.gov/pubmed/34355840 http://dx.doi.org/10.1002/cphc.202100542 |
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author | Mamone, Salvatore Glöggler, Stefan Becker, Stefan Rezaei‐Ghaleh, Nasrollah |
author_facet | Mamone, Salvatore Glöggler, Stefan Becker, Stefan Rezaei‐Ghaleh, Nasrollah |
author_sort | Mamone, Salvatore |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8596873 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85968732021-11-22 Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides Mamone, Salvatore Glöggler, Stefan Becker, Stefan Rezaei‐Ghaleh, Nasrollah Chemphyschem Communications 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. John Wiley and Sons Inc. 2021-08-19 2021-11-04 /pmc/articles/PMC8596873/ /pubmed/34355840 http://dx.doi.org/10.1002/cphc.202100542 Text en © 2021 The Authors. ChemPhysChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Communications Mamone, Salvatore Glöggler, Stefan Becker, Stefan Rezaei‐Ghaleh, Nasrollah Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides |
title | Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides |
title_full | Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides |
title_fullStr | Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides |
title_full_unstemmed | Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides |
title_short | Early Divergence in Misfolding Pathways of Amyloid‐Beta Peptides |
title_sort | early divergence in misfolding pathways of amyloid‐beta peptides |
topic | Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596873/ https://www.ncbi.nlm.nih.gov/pubmed/34355840 http://dx.doi.org/10.1002/cphc.202100542 |
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