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Microglial cell dysregulation in brain aging and neurodegeneration.

von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J - Front Aging Neurosci (2015)

Bottom Line: Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile Santiago, Chile.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Reactivespecies participate in normal cellular function orin pathological mechanisms depending on their overproduction. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), are produced through several mechanisms by the cell: the electron transport chain in mitochondria, various cytosolic and membrane enzymes (i.e., xanthine oxidase (XO), nitric oxide synthase (NOS), NADPH oxidase complex, etc.), as well as exogenously provided by the environment. At the same time, cells have several antioxidant defense mechanisms for detoxifying ROS and RNS, including enzymes (i.e., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and nonenzymatic antioxidants (i.e., reduced glutathione (GSH), vitamins E and C. The main generation pathways of ROS and RNS are also shown: the reduction of O2 occurs by diverse mechanisms (i.e., mitochondria, XO, NADPH-oxidase complex) leading to formation of superoxide anion (O2•-); which is easily transformed to hydrogen peroxide (H2O2) either nonenzymatically or by SOD. H2O2 is converted to H2O by CAT, or by GPx, which together with the GR regenerate GSH. In addition, under stress conditions and high concentration of transition metal (i.e., iron ions—Fe), O2 •- can generate hydroxyl radical (OH•), which in turn can react with polyunsaturated fatty acids (PUFAs) and generate peroxyl radical (ROO•). Finally, O2 •- can react with nitric oxide (NO; depending on NOS), producing the highly reactive peroxinitrite (ONOO•) anion, whereas H2O2 is converted to hypochlorous acid (HOCl) by myeloperoxidase (MPO). The balance between oxidants compounds and antioxidant defense determines the end result. Optimal physiologic levels leads to beneficial effects, with ROS and RNS acting as second messengers in intracellular signaling cascades (modulation of gene regulation and signal transduction pathways, mainly by activation of NFκB), regulating several physiological functions (i.e., cognitive and immune functions). However, when overproduction of ROS/RNS is higher than the antioxidant system, the equilibrium status favors oxidant vs. antioxidant reactions, leading to oxidative stress, in which ROS/RNS have harmful effects, because of their reaction with various macromolecules (lipids, proteins and nucleic acids), contributing to cellular and tissue oxidative damage, and the development of age-related impairments. Oxidation products: 3-NT, 3-nitrotyrosine; 8-OHdG, 8-hydroxy-2-deoxyguanosine; malondialdehyde (MDA); alkoxyl radical (RO•).
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Figure 1: Reactivespecies participate in normal cellular function orin pathological mechanisms depending on their overproduction. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), are produced through several mechanisms by the cell: the electron transport chain in mitochondria, various cytosolic and membrane enzymes (i.e., xanthine oxidase (XO), nitric oxide synthase (NOS), NADPH oxidase complex, etc.), as well as exogenously provided by the environment. At the same time, cells have several antioxidant defense mechanisms for detoxifying ROS and RNS, including enzymes (i.e., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and nonenzymatic antioxidants (i.e., reduced glutathione (GSH), vitamins E and C. The main generation pathways of ROS and RNS are also shown: the reduction of O2 occurs by diverse mechanisms (i.e., mitochondria, XO, NADPH-oxidase complex) leading to formation of superoxide anion (O2•-); which is easily transformed to hydrogen peroxide (H2O2) either nonenzymatically or by SOD. H2O2 is converted to H2O by CAT, or by GPx, which together with the GR regenerate GSH. In addition, under stress conditions and high concentration of transition metal (i.e., iron ions—Fe), O2 •- can generate hydroxyl radical (OH•), which in turn can react with polyunsaturated fatty acids (PUFAs) and generate peroxyl radical (ROO•). Finally, O2 •- can react with nitric oxide (NO; depending on NOS), producing the highly reactive peroxinitrite (ONOO•) anion, whereas H2O2 is converted to hypochlorous acid (HOCl) by myeloperoxidase (MPO). The balance between oxidants compounds and antioxidant defense determines the end result. Optimal physiologic levels leads to beneficial effects, with ROS and RNS acting as second messengers in intracellular signaling cascades (modulation of gene regulation and signal transduction pathways, mainly by activation of NFκB), regulating several physiological functions (i.e., cognitive and immune functions). However, when overproduction of ROS/RNS is higher than the antioxidant system, the equilibrium status favors oxidant vs. antioxidant reactions, leading to oxidative stress, in which ROS/RNS have harmful effects, because of their reaction with various macromolecules (lipids, proteins and nucleic acids), contributing to cellular and tissue oxidative damage, and the development of age-related impairments. Oxidation products: 3-NT, 3-nitrotyrosine; 8-OHdG, 8-hydroxy-2-deoxyguanosine; malondialdehyde (MDA); alkoxyl radical (RO•).

Mentions: At the cellular level, shortening of telomeres and activation of tumor suppressor genes, as well as accumulation of DNA damage, oxidative stress, and mild chronic inflammatory activity are characteristic of aging cells. Various tissues, including the brain show an imbalance between pro- and anti-inflammatory cytokine levels. In addition, potentially damaging mediators, such as cytokines, radical species (Figure 1), and eicosanoids among others, are produced in response to the exposure to physical, chemical or biological agents, such as ionic radiation, pollutants, pathogens, etc. (Dröge and Schipper, 2007; Vijg and Campisi, 2008). Both humans and mice show decreased levels of interleukin 10 (IL10; Ye and Johnson, 2001), and increased levels of tumor necrosis factor α (TNFα) and IL1β in the CNS (Lukiw, 2004; Streit et al., 2004a), and IL6 in plasma (Ye and Johnson, 2001; Godbout and Johnson, 2004). In addition, increased transforming growth factor β1 (TGFβ1) mRNA a key cytokine regulator, has been observed in the brain of aged mice and rats (Bye et al., 2001).


Microglial cell dysregulation in brain aging and neurodegeneration.

von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J - Front Aging Neurosci (2015)

Reactivespecies participate in normal cellular function orin pathological mechanisms depending on their overproduction. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), are produced through several mechanisms by the cell: the electron transport chain in mitochondria, various cytosolic and membrane enzymes (i.e., xanthine oxidase (XO), nitric oxide synthase (NOS), NADPH oxidase complex, etc.), as well as exogenously provided by the environment. At the same time, cells have several antioxidant defense mechanisms for detoxifying ROS and RNS, including enzymes (i.e., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and nonenzymatic antioxidants (i.e., reduced glutathione (GSH), vitamins E and C. The main generation pathways of ROS and RNS are also shown: the reduction of O2 occurs by diverse mechanisms (i.e., mitochondria, XO, NADPH-oxidase complex) leading to formation of superoxide anion (O2•-); which is easily transformed to hydrogen peroxide (H2O2) either nonenzymatically or by SOD. H2O2 is converted to H2O by CAT, or by GPx, which together with the GR regenerate GSH. In addition, under stress conditions and high concentration of transition metal (i.e., iron ions—Fe), O2 •- can generate hydroxyl radical (OH•), which in turn can react with polyunsaturated fatty acids (PUFAs) and generate peroxyl radical (ROO•). Finally, O2 •- can react with nitric oxide (NO; depending on NOS), producing the highly reactive peroxinitrite (ONOO•) anion, whereas H2O2 is converted to hypochlorous acid (HOCl) by myeloperoxidase (MPO). The balance between oxidants compounds and antioxidant defense determines the end result. Optimal physiologic levels leads to beneficial effects, with ROS and RNS acting as second messengers in intracellular signaling cascades (modulation of gene regulation and signal transduction pathways, mainly by activation of NFκB), regulating several physiological functions (i.e., cognitive and immune functions). However, when overproduction of ROS/RNS is higher than the antioxidant system, the equilibrium status favors oxidant vs. antioxidant reactions, leading to oxidative stress, in which ROS/RNS have harmful effects, because of their reaction with various macromolecules (lipids, proteins and nucleic acids), contributing to cellular and tissue oxidative damage, and the development of age-related impairments. Oxidation products: 3-NT, 3-nitrotyrosine; 8-OHdG, 8-hydroxy-2-deoxyguanosine; malondialdehyde (MDA); alkoxyl radical (RO•).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507468&req=5

Figure 1: Reactivespecies participate in normal cellular function orin pathological mechanisms depending on their overproduction. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), are produced through several mechanisms by the cell: the electron transport chain in mitochondria, various cytosolic and membrane enzymes (i.e., xanthine oxidase (XO), nitric oxide synthase (NOS), NADPH oxidase complex, etc.), as well as exogenously provided by the environment. At the same time, cells have several antioxidant defense mechanisms for detoxifying ROS and RNS, including enzymes (i.e., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and nonenzymatic antioxidants (i.e., reduced glutathione (GSH), vitamins E and C. The main generation pathways of ROS and RNS are also shown: the reduction of O2 occurs by diverse mechanisms (i.e., mitochondria, XO, NADPH-oxidase complex) leading to formation of superoxide anion (O2•-); which is easily transformed to hydrogen peroxide (H2O2) either nonenzymatically or by SOD. H2O2 is converted to H2O by CAT, or by GPx, which together with the GR regenerate GSH. In addition, under stress conditions and high concentration of transition metal (i.e., iron ions—Fe), O2 •- can generate hydroxyl radical (OH•), which in turn can react with polyunsaturated fatty acids (PUFAs) and generate peroxyl radical (ROO•). Finally, O2 •- can react with nitric oxide (NO; depending on NOS), producing the highly reactive peroxinitrite (ONOO•) anion, whereas H2O2 is converted to hypochlorous acid (HOCl) by myeloperoxidase (MPO). The balance between oxidants compounds and antioxidant defense determines the end result. Optimal physiologic levels leads to beneficial effects, with ROS and RNS acting as second messengers in intracellular signaling cascades (modulation of gene regulation and signal transduction pathways, mainly by activation of NFκB), regulating several physiological functions (i.e., cognitive and immune functions). However, when overproduction of ROS/RNS is higher than the antioxidant system, the equilibrium status favors oxidant vs. antioxidant reactions, leading to oxidative stress, in which ROS/RNS have harmful effects, because of their reaction with various macromolecules (lipids, proteins and nucleic acids), contributing to cellular and tissue oxidative damage, and the development of age-related impairments. Oxidation products: 3-NT, 3-nitrotyrosine; 8-OHdG, 8-hydroxy-2-deoxyguanosine; malondialdehyde (MDA); alkoxyl radical (RO•).
Mentions: At the cellular level, shortening of telomeres and activation of tumor suppressor genes, as well as accumulation of DNA damage, oxidative stress, and mild chronic inflammatory activity are characteristic of aging cells. Various tissues, including the brain show an imbalance between pro- and anti-inflammatory cytokine levels. In addition, potentially damaging mediators, such as cytokines, radical species (Figure 1), and eicosanoids among others, are produced in response to the exposure to physical, chemical or biological agents, such as ionic radiation, pollutants, pathogens, etc. (Dröge and Schipper, 2007; Vijg and Campisi, 2008). Both humans and mice show decreased levels of interleukin 10 (IL10; Ye and Johnson, 2001), and increased levels of tumor necrosis factor α (TNFα) and IL1β in the CNS (Lukiw, 2004; Streit et al., 2004a), and IL6 in plasma (Ye and Johnson, 2001; Godbout and Johnson, 2004). In addition, increased transforming growth factor β1 (TGFβ1) mRNA a key cytokine regulator, has been observed in the brain of aged mice and rats (Bye et al., 2001).

Bottom Line: Interestingly, whereas the regulatory cytokine TGFβ1 is also increased in the aged brain, neuroinflammation persists.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile Santiago, Chile.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus