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Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress
Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive declin...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437142/ https://www.ncbi.nlm.nih.gov/pubmed/32903435 http://dx.doi.org/10.3389/fnmol.2020.00138 |
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author | Govindarajulu, Manoj Pinky, Priyanka D. Steinke, Ian Bloemer, Jenna Ramesh, Sindhu Kariharan, Thiruchelvan Rella, Robert T. Bhattacharya, Subhrajit Dhanasekaran, Muralikrishnan Suppiramaniam, Vishnu Amin, Rajesh H. |
author_facet | Govindarajulu, Manoj Pinky, Priyanka D. Steinke, Ian Bloemer, Jenna Ramesh, Sindhu Kariharan, Thiruchelvan Rella, Robert T. Bhattacharya, Subhrajit Dhanasekaran, Muralikrishnan Suppiramaniam, Vishnu Amin, Rajesh H. |
author_sort | Govindarajulu, Manoj |
collection | PubMed |
description | Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer’s model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention. |
format | Online Article Text |
id | pubmed-7437142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74371422020-09-03 Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress Govindarajulu, Manoj Pinky, Priyanka D. Steinke, Ian Bloemer, Jenna Ramesh, Sindhu Kariharan, Thiruchelvan Rella, Robert T. Bhattacharya, Subhrajit Dhanasekaran, Muralikrishnan Suppiramaniam, Vishnu Amin, Rajesh H. Front Mol Neurosci Neuroscience Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer’s model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention. Frontiers Media S.A. 2020-08-12 /pmc/articles/PMC7437142/ /pubmed/32903435 http://dx.doi.org/10.3389/fnmol.2020.00138 Text en Copyright © 2020 Govindarajulu, Pinky, Steinke, Bloemer, Ramesh, Kariharan, Rella, Bhattacharya, Dhanasekaran, Suppiramaniam and Amin. 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 Govindarajulu, Manoj Pinky, Priyanka D. Steinke, Ian Bloemer, Jenna Ramesh, Sindhu Kariharan, Thiruchelvan Rella, Robert T. Bhattacharya, Subhrajit Dhanasekaran, Muralikrishnan Suppiramaniam, Vishnu Amin, Rajesh H. Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress |
title | Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress |
title_full | Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress |
title_fullStr | Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress |
title_full_unstemmed | Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress |
title_short | Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress |
title_sort | gut metabolite tmao induces synaptic plasticity deficits by promoting endoplasmic reticulum stress |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437142/ https://www.ncbi.nlm.nih.gov/pubmed/32903435 http://dx.doi.org/10.3389/fnmol.2020.00138 |
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