Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates
[Image: see text] Amyloid-beta (Aβ) deposition as senile plaques is a pathological hallmark of Alzheimer’s disease (AD). AD is characterized by a large level of heterogeneity in amyloid pathology, whose molecular origin is poorly understood. Here, we employ NMR spectroscopy and MD simulation at ambi...
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ftpubmed:oai:pubmedcentral.nih.gov:9940190 2023-05-15T15:04:07+02:00 Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates Rezaei-Ghaleh, Nasrollah Amininasab, Mehriar Giller, Karin Becker, Stefan 2023-02-03 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940190/ http://www.ncbi.nlm.nih.gov/pubmed/36734539 https://doi.org/10.1021/acs.jpclett.2c03729 en eng American Chemical Society http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940190/ http://www.ncbi.nlm.nih.gov/pubmed/36734539 http://dx.doi.org/10.1021/acs.jpclett.2c03729 © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). CC-BY J Phys Chem Lett Text 2023 ftpubmed https://doi.org/10.1021/acs.jpclett.2c03729 2023-02-26T01:43:07Z [Image: see text] Amyloid-beta (Aβ) deposition as senile plaques is a pathological hallmark of Alzheimer’s disease (AD). AD is characterized by a large level of heterogeneity in amyloid pathology, whose molecular origin is poorly understood. Here, we employ NMR spectroscopy and MD simulation at ambient and high pressures and investigate how AD-related mutations in Aβ peptide influence the stability of Aβ aggregates. The pressure-induced monomer dissociation from Aβ aggregates monitored by NMR demonstrated that the Iowa (D23N), Arctic (E22G), and Osaka (ΔE22) mutations altered the pressure stability of Aβ40 aggregates in distinct manners. While the NMR data of monomeric Aβ40 showed only small localized effects of mutations, the MD simulation of mutated Aβ fibrils revealed their distinct susceptibility to elevated pressure. Our data propose a structural basis for the distinct stability of various Aβ fibrils and highlights “stability” as a molecular property potentially contributing to the large heterogeneity of amyloid pathology in AD. Text Arctic PubMed Central (PMC) Arctic The Journal of Physical Chemistry Letters 14 6 1427 1435 |
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[Image: see text] Amyloid-beta (Aβ) deposition as senile plaques is a pathological hallmark of Alzheimer’s disease (AD). AD is characterized by a large level of heterogeneity in amyloid pathology, whose molecular origin is poorly understood. Here, we employ NMR spectroscopy and MD simulation at ambient and high pressures and investigate how AD-related mutations in Aβ peptide influence the stability of Aβ aggregates. The pressure-induced monomer dissociation from Aβ aggregates monitored by NMR demonstrated that the Iowa (D23N), Arctic (E22G), and Osaka (ΔE22) mutations altered the pressure stability of Aβ40 aggregates in distinct manners. While the NMR data of monomeric Aβ40 showed only small localized effects of mutations, the MD simulation of mutated Aβ fibrils revealed their distinct susceptibility to elevated pressure. Our data propose a structural basis for the distinct stability of various Aβ fibrils and highlights “stability” as a molecular property potentially contributing to the large heterogeneity of amyloid pathology in AD. |
format |
Text |
author |
Rezaei-Ghaleh, Nasrollah Amininasab, Mehriar Giller, Karin Becker, Stefan |
spellingShingle |
Rezaei-Ghaleh, Nasrollah Amininasab, Mehriar Giller, Karin Becker, Stefan Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates |
author_facet |
Rezaei-Ghaleh, Nasrollah Amininasab, Mehriar Giller, Karin Becker, Stefan |
author_sort |
Rezaei-Ghaleh, Nasrollah |
title |
Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates |
title_short |
Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates |
title_full |
Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates |
title_fullStr |
Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates |
title_full_unstemmed |
Familial Alzheimer’s Disease-Related Mutations Differentially Alter Stability of Amyloid-Beta Aggregates |
title_sort |
familial alzheimer’s disease-related mutations differentially alter stability of amyloid-beta aggregates |
publisher |
American Chemical Society |
publishDate |
2023 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940190/ http://www.ncbi.nlm.nih.gov/pubmed/36734539 https://doi.org/10.1021/acs.jpclett.2c03729 |
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Arctic |
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Arctic |
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Arctic |
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Arctic |
op_source |
J Phys Chem Lett |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940190/ http://www.ncbi.nlm.nih.gov/pubmed/36734539 http://dx.doi.org/10.1021/acs.jpclett.2c03729 |
op_rights |
© 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
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CC-BY |
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https://doi.org/10.1021/acs.jpclett.2c03729 |
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The Journal of Physical Chemistry Letters |
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14 |
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6 |
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1427 |
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1435 |
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1766335925211627520 |