Microglial cell dysregulation in Brain Aging and Neurodegeneration.
Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo 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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-07-01
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| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnagi.2015.00124/full |
| _version_ | 1818173411689496576 |
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| author | Rommy eVon Bernhardi Laura eEugenin-von Bernhardi Jaime eEugenin |
| author_facet | Rommy eVon Bernhardi Laura eEugenin-von Bernhardi Jaime eEugenin |
| author_sort | Rommy eVon Bernhardi |
| collection | DOAJ |
| description | Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo 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 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 a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegeneration. |
| first_indexed | 2024-12-11T19:28:05Z |
| format | Article |
| id | doaj.art-ce683279bb3246fab19afe9bec7f0660 |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-11T19:28:05Z |
| publishDate | 2015-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-ce683279bb3246fab19afe9bec7f06602022-12-22T00:53:22ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652015-07-01710.3389/fnagi.2015.00124140542Microglial cell dysregulation in Brain Aging and Neurodegeneration.Rommy eVon Bernhardi0Laura eEugenin-von Bernhardi1Jaime eEugenin2Pontificia Universidad Catolica de Chile School of MedicinePontificia Universidad Catolica de Chile School of MedicineUniversidad de Santiago (USACH)Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergo 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 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 a reduction of protective activation and a facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegeneration.http://journal.frontiersin.org/Journal/10.3389/fnagi.2015.00124/fullAgingCytokinesMitochondriaNeurodegenerative DiseasesReactive Oxygen Speciesglia |
| spellingShingle | Rommy eVon Bernhardi Laura eEugenin-von Bernhardi Jaime eEugenin Microglial cell dysregulation in Brain Aging and Neurodegeneration. Frontiers in Aging Neuroscience Aging Cytokines Mitochondria Neurodegenerative Diseases Reactive Oxygen Species glia |
| 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 | Aging Cytokines Mitochondria Neurodegenerative Diseases Reactive Oxygen Species glia |
| url | http://journal.frontiersin.org/Journal/10.3389/fnagi.2015.00124/full |
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