Cargando…
Microglial cell dysregulation in brain aging and neurodegeneration
Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheim...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507468/ https://www.ncbi.nlm.nih.gov/pubmed/26257642 http://dx.doi.org/10.3389/fnagi.2015.00124 |
_version_ | 1782381795147251712 |
---|---|
author | von Bernhardi, Rommy Eugenín-von Bernhardi, Laura Eugenín, Jaime |
author_facet | von Bernhardi, Rommy Eugenín-von Bernhardi, Laura Eugenín, Jaime |
author_sort | von Bernhardi, Rommy |
collection | PubMed |
description | Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide (NO) secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in the reduction of protective activation and the facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-4507468 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-45074682015-08-07 Microglial cell dysregulation in brain aging and neurodegeneration von Bernhardi, Rommy Eugenín-von Bernhardi, Laura Eugenín, Jaime Front Aging Neurosci Neuroscience Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide (NO) secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1β, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGFβ1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGFβ1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGFβ1-Smad3 pathway, could result in the reduction of protective activation and the facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegenerative diseases. Frontiers Media S.A. 2015-07-20 /pmc/articles/PMC4507468/ /pubmed/26257642 http://dx.doi.org/10.3389/fnagi.2015.00124 Text en Copyright © 2015 von Bernhardi, Eugenín-von Bernhardi and Eugenín. 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 and reproduction in other forums is permitted, provided the original author(s) or licensor 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 von Bernhardi, Rommy Eugenín-von Bernhardi, Laura Eugenín, Jaime Microglial cell dysregulation in brain aging and neurodegeneration |
title | Microglial cell dysregulation in brain aging and neurodegeneration |
title_full | Microglial cell dysregulation in brain aging and neurodegeneration |
title_fullStr | Microglial cell dysregulation in brain aging and neurodegeneration |
title_full_unstemmed | Microglial cell dysregulation in brain aging and neurodegeneration |
title_short | Microglial cell dysregulation in brain aging and neurodegeneration |
title_sort | microglial cell dysregulation in brain aging and neurodegeneration |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4507468/ https://www.ncbi.nlm.nih.gov/pubmed/26257642 http://dx.doi.org/10.3389/fnagi.2015.00124 |
work_keys_str_mv | AT vonbernhardirommy microglialcelldysregulationinbrainagingandneurodegeneration AT eugeninvonbernhardilaura microglialcelldysregulationinbrainagingandneurodegeneration AT eugeninjaime microglialcelldysregulationinbrainagingandneurodegeneration |