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Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole’s effect on amyloid beta (Aβ) pathology, a major histopatho...

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Autores principales: Okamoto, Masahiro, Gray, Jason D., Larson, Chloe S., Kazim, Syed Faraz, Soya, Hideaki, McEwen, Bruce S., Pereira, Ana C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092426/
https://www.ncbi.nlm.nih.gov/pubmed/30108205
http://dx.doi.org/10.1038/s41398-018-0201-z
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author Okamoto, Masahiro
Gray, Jason D.
Larson, Chloe S.
Kazim, Syed Faraz
Soya, Hideaki
McEwen, Bruce S.
Pereira, Ana C.
author_facet Okamoto, Masahiro
Gray, Jason D.
Larson, Chloe S.
Kazim, Syed Faraz
Soya, Hideaki
McEwen, Bruce S.
Pereira, Ana C.
author_sort Okamoto, Masahiro
collection PubMed
description Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole’s effect on amyloid beta (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an Aβ mouse model of early-onset familial AD.
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spelling pubmed-60924262018-08-15 Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease Okamoto, Masahiro Gray, Jason D. Larson, Chloe S. Kazim, Syed Faraz Soya, Hideaki McEwen, Bruce S. Pereira, Ana C. Transl Psychiatry Article Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole’s effect on amyloid beta (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an Aβ mouse model of early-onset familial AD. Nature Publishing Group UK 2018-08-14 /pmc/articles/PMC6092426/ /pubmed/30108205 http://dx.doi.org/10.1038/s41398-018-0201-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Okamoto, Masahiro
Gray, Jason D.
Larson, Chloe S.
Kazim, Syed Faraz
Soya, Hideaki
McEwen, Bruce S.
Pereira, Ana C.
Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease
title Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease
title_full Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease
title_fullStr Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease
title_full_unstemmed Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease
title_short Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease
title_sort riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092426/
https://www.ncbi.nlm.nih.gov/pubmed/30108205
http://dx.doi.org/10.1038/s41398-018-0201-z
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