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Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging
Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer’s disease. The...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135881/ https://www.ncbi.nlm.nih.gov/pubmed/30237765 http://dx.doi.org/10.3389/fnagi.2018.00263 |
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author | Duval, Nathan Vacano, Guido N. Patterson, David |
author_facet | Duval, Nathan Vacano, Guido N. Patterson, David |
author_sort | Duval, Nathan |
collection | PubMed |
description | Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer’s disease. The Ts65Dn mouse is the best characterized model of DS and has many features reminiscent of DS, including developmental anomalies and age-related neurodegeneration. The mouse carries a partial triplication of mouse chromosome 16 containing roughly 100 genes syntenic to human chromosome 21 genes. We hypothesized that there would be differences in brain metabolites with trisomy and age, and that long-term treatment with rapamycin, mechanistic target of rapamycin (mTOR) inhibitor and immunosuppressant, would correct these differences. Using HPLC coupled with electrochemical detection, we identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age. These include homovanillic acid, norepinephrine, and kynurenine. In addition, we demonstrate that prolonged treatment with rapamycin reduces accumulation of toxic metabolites (such as 6-hydroxymelatonin and 3-hydroxykynurenine) in aged mice. |
format | Online Article Text |
id | pubmed-6135881 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61358812018-09-20 Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging Duval, Nathan Vacano, Guido N. Patterson, David Front Aging Neurosci Neuroscience Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. Individuals with DS exhibit changes in neurochemistry and neuroanatomy that worsen with age, neurological delay in learning and memory, and predisposition to Alzheimer’s disease. The Ts65Dn mouse is the best characterized model of DS and has many features reminiscent of DS, including developmental anomalies and age-related neurodegeneration. The mouse carries a partial triplication of mouse chromosome 16 containing roughly 100 genes syntenic to human chromosome 21 genes. We hypothesized that there would be differences in brain metabolites with trisomy and age, and that long-term treatment with rapamycin, mechanistic target of rapamycin (mTOR) inhibitor and immunosuppressant, would correct these differences. Using HPLC coupled with electrochemical detection, we identified differences in levels of metabolites involved in dopaminergic, serotonergic, and kynurenine pathways in trisomic mice that are exacerbated with age. These include homovanillic acid, norepinephrine, and kynurenine. In addition, we demonstrate that prolonged treatment with rapamycin reduces accumulation of toxic metabolites (such as 6-hydroxymelatonin and 3-hydroxykynurenine) in aged mice. Frontiers Media S.A. 2018-09-06 /pmc/articles/PMC6135881/ /pubmed/30237765 http://dx.doi.org/10.3389/fnagi.2018.00263 Text en Copyright © 2018 Duval, Vacano and Patterson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Duval, Nathan Vacano, Guido N. Patterson, David Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging |
title | Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging |
title_full | Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging |
title_fullStr | Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging |
title_full_unstemmed | Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging |
title_short | Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging |
title_sort | rapamycin treatment ameliorates age-related accumulation of toxic metabolic intermediates in brains of the ts65dn mouse model of down syndrome and aging |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135881/ https://www.ncbi.nlm.nih.gov/pubmed/30237765 http://dx.doi.org/10.3389/fnagi.2018.00263 |
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