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Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture
The remarkable co-localization of highly pro-inflammatory lipopolysaccharide (LPS) with sporadic Alzheimer’s disease (AD)-affected neuronal nuclei suggests that there may be some novel pathogenic contribution of this heat stable neurotoxin to neuronal activity and neuron-specific gene expression. In...
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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/PMC6289986/ https://www.ncbi.nlm.nih.gov/pubmed/30568571 http://dx.doi.org/10.3389/fnins.2018.00896 |
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author | Lukiw, Walter J. Cong, Lin Jaber, Vivian Zhao, Yuhai |
author_facet | Lukiw, Walter J. Cong, Lin Jaber, Vivian Zhao, Yuhai |
author_sort | Lukiw, Walter J. |
collection | PubMed |
description | The remarkable co-localization of highly pro-inflammatory lipopolysaccharide (LPS) with sporadic Alzheimer’s disease (AD)-affected neuronal nuclei suggests that there may be some novel pathogenic contribution of this heat stable neurotoxin to neuronal activity and neuron-specific gene expression. In this communication we show for the first time: (i) the association and envelopment of sporadic AD neuronal nuclei with LPS in multiple AD neocortical tissue samples; and (ii) a selective repression in the output of neuron-specific neurofilament light (NF-L) chain messenger RNA (mRNA), perhaps as a consequence of this association. The down-regulation of NF-L mRNA and protein is a characteristic attribute of AD brain and accompanies neuronal atrophy and an associated loss of neuronal architecture with synaptic deficits. To study this phenomenon further, human neuronal-glial (HNG) cells in primary culture were incubated with LPS, and DNA arrays, Northern, Western, and ELISA analyses were used to quantify transcription patterns for the three member neuron-specific intermediate filament-gene family NF-H, NF-M, and NF-L. As in sporadic AD limbic-regions, down-regulated transcription products for the NF-L intermediate filament protein was significant. These results support our novel hypothesis: (i) that internally sourced, microbiome-derived neurotoxins such as LPS contribute to a progressive disruption in the read-out of neuron-specific genetic-information; (ii) that the presence of LPS-enveloped neuronal nuclei is associated with a down-regulation in NF-L expression, a key neuron-specific cytoskeletal component; and (iii) this may have a bearing on progressive neuronal atrophy, loss of synaptic-contact and disruption of neuronal architecture, all of which are characteristic pathological features of sporadic-AD brain. This is the first report that provides evidence for a neuron-specific effect of a human GI-tract microbiome-derived neurotoxin on decreased NF-L abundance in both sporadic AD temporal lobe neocortex in vivo and in LPS-stressed HNG cells in vitro. |
format | Online Article Text |
id | pubmed-6289986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62899862018-12-19 Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture Lukiw, Walter J. Cong, Lin Jaber, Vivian Zhao, Yuhai Front Neurosci Neuroscience The remarkable co-localization of highly pro-inflammatory lipopolysaccharide (LPS) with sporadic Alzheimer’s disease (AD)-affected neuronal nuclei suggests that there may be some novel pathogenic contribution of this heat stable neurotoxin to neuronal activity and neuron-specific gene expression. In this communication we show for the first time: (i) the association and envelopment of sporadic AD neuronal nuclei with LPS in multiple AD neocortical tissue samples; and (ii) a selective repression in the output of neuron-specific neurofilament light (NF-L) chain messenger RNA (mRNA), perhaps as a consequence of this association. The down-regulation of NF-L mRNA and protein is a characteristic attribute of AD brain and accompanies neuronal atrophy and an associated loss of neuronal architecture with synaptic deficits. To study this phenomenon further, human neuronal-glial (HNG) cells in primary culture were incubated with LPS, and DNA arrays, Northern, Western, and ELISA analyses were used to quantify transcription patterns for the three member neuron-specific intermediate filament-gene family NF-H, NF-M, and NF-L. As in sporadic AD limbic-regions, down-regulated transcription products for the NF-L intermediate filament protein was significant. These results support our novel hypothesis: (i) that internally sourced, microbiome-derived neurotoxins such as LPS contribute to a progressive disruption in the read-out of neuron-specific genetic-information; (ii) that the presence of LPS-enveloped neuronal nuclei is associated with a down-regulation in NF-L expression, a key neuron-specific cytoskeletal component; and (iii) this may have a bearing on progressive neuronal atrophy, loss of synaptic-contact and disruption of neuronal architecture, all of which are characteristic pathological features of sporadic-AD brain. This is the first report that provides evidence for a neuron-specific effect of a human GI-tract microbiome-derived neurotoxin on decreased NF-L abundance in both sporadic AD temporal lobe neocortex in vivo and in LPS-stressed HNG cells in vitro. Frontiers Media S.A. 2018-12-05 /pmc/articles/PMC6289986/ /pubmed/30568571 http://dx.doi.org/10.3389/fnins.2018.00896 Text en Copyright © 2018 Lukiw, Cong, Jaber and Zhao. 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 Lukiw, Walter J. Cong, Lin Jaber, Vivian Zhao, Yuhai Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture |
title | Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture |
title_full | Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture |
title_fullStr | Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture |
title_full_unstemmed | Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture |
title_short | Microbiome-Derived Lipopolysaccharide (LPS) Selectively Inhibits Neurofilament Light Chain (NF-L) Gene Expression in Human Neuronal-Glial (HNG) Cells in Primary Culture |
title_sort | microbiome-derived lipopolysaccharide (lps) selectively inhibits neurofilament light chain (nf-l) gene expression in human neuronal-glial (hng) cells in primary culture |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289986/ https://www.ncbi.nlm.nih.gov/pubmed/30568571 http://dx.doi.org/10.3389/fnins.2018.00896 |
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