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The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro

Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on th...

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Autores principales: Nedaei, Hadi, Rezaei-Ghaleh, Nasrollah, Giller, Karin, Becker, Stefan, Karami, Leila, Moosavi-Movahedi, Ali Akbar, Griesinger, Christian, Saboury, Ali Akbar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898965/
https://www.ncbi.nlm.nih.gov/pubmed/35104501
http://dx.doi.org/10.1016/j.jbc.2022.101662
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author Nedaei, Hadi
Rezaei-Ghaleh, Nasrollah
Giller, Karin
Becker, Stefan
Karami, Leila
Moosavi-Movahedi, Ali Akbar
Griesinger, Christian
Saboury, Ali Akbar
author_facet Nedaei, Hadi
Rezaei-Ghaleh, Nasrollah
Giller, Karin
Becker, Stefan
Karami, Leila
Moosavi-Movahedi, Ali Akbar
Griesinger, Christian
Saboury, Ali Akbar
author_sort Nedaei, Hadi
collection PubMed
description Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on the production of cerebral Aβ. A meta-analysis on humans showed moderate effects in the short term but no improvement in the Alzheimer's Disease Assessment Scale—Cognitive Subscale behavioral test. Here, we explore a potential direct effect of Ator on Aβ42 aggregation. Using NMR-based monomer consumption assays and CD spectroscopy, we observed a promoting effect of Ator in its original form (Ator-calcium) on Aβ42 aggregation, as expected because of the presence of calcium ions. The effect was reversed when applying a CaCO(3)-based calcium ion scavenging method, which was validated by the aforementioned methods as well as thioflavin-T fluorescence assays and transmission electron microscopy. We found that the aggregation was inhibited significantly when the concentration of calcium-free Ator exceeded that of Aβ by at least a factor of 2. The (1)H–(15)N heteronuclear single quantum correlation and saturation-transfer difference NMR data suggest that calcium-free Ator exerts its effect through interaction with the (16)KLVF(19) binding site on the Aβ peptide via its aromatic rings as well as hydroxyl and methyl groups. On the other hand, molecular dynamics simulations confirmed that the increasing concentration of Ator is necessary for the inhibition of the conformational transition of Aβ from an α-helix-dominant to a β-sheet-dominant structure.
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spelling pubmed-88989652022-03-11 The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro Nedaei, Hadi Rezaei-Ghaleh, Nasrollah Giller, Karin Becker, Stefan Karami, Leila Moosavi-Movahedi, Ali Akbar Griesinger, Christian Saboury, Ali Akbar J Biol Chem Research Article Alzheimer's disease is characterized by the presence of extraneuronal amyloid plaques composed of amyloid-beta (Aβ) fibrillar aggregates in the brains of patients. In mouse models, it has previously been shown that atorvastatin (Ator), a cholesterol-lowering drug, has some reducing effect on the production of cerebral Aβ. A meta-analysis on humans showed moderate effects in the short term but no improvement in the Alzheimer's Disease Assessment Scale—Cognitive Subscale behavioral test. Here, we explore a potential direct effect of Ator on Aβ42 aggregation. Using NMR-based monomer consumption assays and CD spectroscopy, we observed a promoting effect of Ator in its original form (Ator-calcium) on Aβ42 aggregation, as expected because of the presence of calcium ions. The effect was reversed when applying a CaCO(3)-based calcium ion scavenging method, which was validated by the aforementioned methods as well as thioflavin-T fluorescence assays and transmission electron microscopy. We found that the aggregation was inhibited significantly when the concentration of calcium-free Ator exceeded that of Aβ by at least a factor of 2. The (1)H–(15)N heteronuclear single quantum correlation and saturation-transfer difference NMR data suggest that calcium-free Ator exerts its effect through interaction with the (16)KLVF(19) binding site on the Aβ peptide via its aromatic rings as well as hydroxyl and methyl groups. On the other hand, molecular dynamics simulations confirmed that the increasing concentration of Ator is necessary for the inhibition of the conformational transition of Aβ from an α-helix-dominant to a β-sheet-dominant structure. American Society for Biochemistry and Molecular Biology 2022-01-30 /pmc/articles/PMC8898965/ /pubmed/35104501 http://dx.doi.org/10.1016/j.jbc.2022.101662 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Nedaei, Hadi
Rezaei-Ghaleh, Nasrollah
Giller, Karin
Becker, Stefan
Karami, Leila
Moosavi-Movahedi, Ali Akbar
Griesinger, Christian
Saboury, Ali Akbar
The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
title The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
title_full The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
title_fullStr The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
title_full_unstemmed The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
title_short The calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
title_sort calcium-free form of atorvastatin inhibits amyloid-β(1–42) aggregation in vitro
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8898965/
https://www.ncbi.nlm.nih.gov/pubmed/35104501
http://dx.doi.org/10.1016/j.jbc.2022.101662
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