Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology
In aging individuals, both protective as well as regulatory immune functions are declining, resulting in an increased susceptibility to infections as well as to autoimmunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2-deficiency in immune cell subsets has been shown to be associat...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2017-07-01
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Series: | Frontiers in Immunology |
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Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00844/full |
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doaj-ba9246be28e8422ea9d46a294d4cbeac |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Helena Radbruch Ronja Mothes Ronja Mothes Daniel Bremer Stefanie Seifert Ralf Köhler Julian Pohlan Julian Pohlan Lennard Ostendorf Robert Günther Ruth Leben Werner Stenzel Raluca Aura Niesner Anja E. Hauser Anja E. Hauser |
spellingShingle |
Helena Radbruch Ronja Mothes Ronja Mothes Daniel Bremer Stefanie Seifert Ralf Köhler Julian Pohlan Julian Pohlan Lennard Ostendorf Robert Günther Ruth Leben Werner Stenzel Raluca Aura Niesner Anja E. Hauser Anja E. Hauser Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology Frontiers in Immunology aging NADPH oxidases microglia astrocytes Alzheimer’s disease cerebral amyloid angiopathy |
author_facet |
Helena Radbruch Ronja Mothes Ronja Mothes Daniel Bremer Stefanie Seifert Ralf Köhler Julian Pohlan Julian Pohlan Lennard Ostendorf Robert Günther Ruth Leben Werner Stenzel Raluca Aura Niesner Anja E. Hauser Anja E. Hauser |
author_sort |
Helena Radbruch |
title |
Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology |
title_short |
Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology |
title_full |
Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology |
title_fullStr |
Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology |
title_full_unstemmed |
Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology |
title_sort |
analyzing nicotinamide adenine dinucleotide phosphate oxidase activation in aging and vascular amyloid pathology |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2017-07-01 |
description |
In aging individuals, both protective as well as regulatory immune functions are declining, resulting in an increased susceptibility to infections as well as to autoimmunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2-deficiency in immune cell subsets has been shown to be associated with aging. Using intravital marker-free NAD(P)H-fluorescence lifetime imaging, we have previously identified microglia/myeloid cells and astrocytes as main cellular sources of NADPH oxidase (NOX) activity in the CNS during neuroinflammation, due to an overactivation of NOX. The overactivated NOX enzymes catalyze the massive production of the highly reactive O2−, which initiates in a chain reaction the overproduction of diverse reactive oxygen species (ROS). Age-dependent oxidative distress levels in the brain and their cellular sources are not known. Furthermore, it is unclear whether in age-dependent diseases oxidative distress is initiated by overproduction of ROS or by a decrease in antioxidant capacity, subsequently leading to neurodegeneration in the CNS. Here, we compare the activation level of NOX enzymes in the cerebral cortex of young and aged mice as well as in a model of vascular amyloid pathology. Despite the fact that a striking change in the morphology of microglia can be detected between young and aged individuals, we find comparable low-level NOX activation both in young and old mice. In contrast, aged mice with the human APPE693Q mutation, a model for cerebral amyloid angiopathy (CAA), displayed increased focal NOX overactivation in the brain cortex, especially in tissue areas around the vessels. Despite activated morphology in microglia, NOX overactivation was detected only in a small fraction of these cells, in contrast to other pathologies with overt inflammation as experimental autoimmune encephalomyelitis (EAE) or glioblastoma. Similar to these pathologies, the astrocytes majorly contribute to the NOX overactivation in the brain cortex during CAA. Together, these findings emphasize the role of other cellular sources of activated NOX than phagocytes not only during EAE but also in models of amyloid pathology. Moreover, they may strengthen the hypothesis that microglia/monocytes show a diminished potential for clearance of amyloid beta protein. |
topic |
aging NADPH oxidases microglia astrocytes Alzheimer’s disease cerebral amyloid angiopathy |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2017.00844/full |
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doaj-ba9246be28e8422ea9d46a294d4cbeac2020-11-24T22:31:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-07-01810.3389/fimmu.2017.00844246260Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid PathologyHelena Radbruch0Ronja Mothes1Ronja Mothes2Daniel Bremer3Stefanie Seifert4Ralf Köhler5Julian Pohlan6Julian Pohlan7Lennard Ostendorf8Robert Günther9Ruth Leben10Werner Stenzel11Raluca Aura Niesner12Anja E. Hauser13Anja E. Hauser14Department of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, GermanyDepartment of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyDepartment of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, GermanyImmune Dynamics, Deutsches Rheuma-Forschungszentrum (DRFZ), A Leibniz Institute, Berlin, GermanyDepartment of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyDepartment of Neuropathology, Charité – Universitätsmedizin Berlin, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyGerman Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, GermanyImmune Dynamics, Charité – Universitätsmedizin Berlin, Berlin, GermanyIn aging individuals, both protective as well as regulatory immune functions are declining, resulting in an increased susceptibility to infections as well as to autoimmunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2-deficiency in immune cell subsets has been shown to be associated with aging. Using intravital marker-free NAD(P)H-fluorescence lifetime imaging, we have previously identified microglia/myeloid cells and astrocytes as main cellular sources of NADPH oxidase (NOX) activity in the CNS during neuroinflammation, due to an overactivation of NOX. The overactivated NOX enzymes catalyze the massive production of the highly reactive O2−, which initiates in a chain reaction the overproduction of diverse reactive oxygen species (ROS). Age-dependent oxidative distress levels in the brain and their cellular sources are not known. Furthermore, it is unclear whether in age-dependent diseases oxidative distress is initiated by overproduction of ROS or by a decrease in antioxidant capacity, subsequently leading to neurodegeneration in the CNS. Here, we compare the activation level of NOX enzymes in the cerebral cortex of young and aged mice as well as in a model of vascular amyloid pathology. Despite the fact that a striking change in the morphology of microglia can be detected between young and aged individuals, we find comparable low-level NOX activation both in young and old mice. In contrast, aged mice with the human APPE693Q mutation, a model for cerebral amyloid angiopathy (CAA), displayed increased focal NOX overactivation in the brain cortex, especially in tissue areas around the vessels. Despite activated morphology in microglia, NOX overactivation was detected only in a small fraction of these cells, in contrast to other pathologies with overt inflammation as experimental autoimmune encephalomyelitis (EAE) or glioblastoma. Similar to these pathologies, the astrocytes majorly contribute to the NOX overactivation in the brain cortex during CAA. Together, these findings emphasize the role of other cellular sources of activated NOX than phagocytes not only during EAE but also in models of amyloid pathology. Moreover, they may strengthen the hypothesis that microglia/monocytes show a diminished potential for clearance of amyloid beta protein.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00844/fullagingNADPH oxidasesmicrogliaastrocytesAlzheimer’s diseasecerebral amyloid angiopathy |