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Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast

A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer’s disease, this study has focused on how simvastatin influences the turnover...

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Autores principales: Dhakal, Sudip, Subhan, Mishal, Fraser, Joshua M., Gardiner, Kenneth, Macreadie, Ian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678968/
https://www.ncbi.nlm.nih.gov/pubmed/31330953
http://dx.doi.org/10.3390/ijms20143531
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author Dhakal, Sudip
Subhan, Mishal
Fraser, Joshua M.
Gardiner, Kenneth
Macreadie, Ian
author_facet Dhakal, Sudip
Subhan, Mishal
Fraser, Joshua M.
Gardiner, Kenneth
Macreadie, Ian
author_sort Dhakal, Sudip
collection PubMed
description A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer’s disease, this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, Saccharomyces cerevisiae. Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aβ42 turnover. In this study the proportion of cells having GFP fused to Aβ after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aβ42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aβ42 fused to GFP. The levels of native Aβ42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aβ42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aβ42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance.
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spelling pubmed-66789682019-08-19 Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast Dhakal, Sudip Subhan, Mishal Fraser, Joshua M. Gardiner, Kenneth Macreadie, Ian Int J Mol Sci Article A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer’s disease, this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, Saccharomyces cerevisiae. Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aβ42 turnover. In this study the proportion of cells having GFP fused to Aβ after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aβ42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aβ42 fused to GFP. The levels of native Aβ42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aβ42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aβ42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance. MDPI 2019-07-19 /pmc/articles/PMC6678968/ /pubmed/31330953 http://dx.doi.org/10.3390/ijms20143531 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dhakal, Sudip
Subhan, Mishal
Fraser, Joshua M.
Gardiner, Kenneth
Macreadie, Ian
Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast
title Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast
title_full Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast
title_fullStr Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast
title_full_unstemmed Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast
title_short Simvastatin Efficiently Reduces Levels of Alzheimer’s Amyloid Beta in Yeast
title_sort simvastatin efficiently reduces levels of alzheimer’s amyloid beta in yeast
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678968/
https://www.ncbi.nlm.nih.gov/pubmed/31330953
http://dx.doi.org/10.3390/ijms20143531
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