Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism
Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, high levels of p38MAPK are present in the brain during no...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2019-06-01
|
| Series: | Frontiers in Neurology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2019.00675/full |
| _version_ | 1819000137257582592 |
|---|---|
| author | Adrián Martín-Segura Adrián Martín-Segura Álvaro Casadomé-Perales Pietro Fazzari Pietro Fazzari José Manuel Mas Laura Artigas Raquel Valls Angel R. Nebreda Angel R. Nebreda Carlos G. Dotti |
| author_facet | Adrián Martín-Segura Adrián Martín-Segura Álvaro Casadomé-Perales Pietro Fazzari Pietro Fazzari José Manuel Mas Laura Artigas Raquel Valls Angel R. Nebreda Angel R. Nebreda Carlos G. Dotti |
| author_sort | Adrián Martín-Segura |
| collection | DOAJ |
| description | Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, high levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes. |
| first_indexed | 2024-12-20T22:28:32Z |
| format | Article |
| id | doaj.art-51d53101edb548d5bfcae6feb9c2312e |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-12-20T22:28:32Z |
| publishDate | 2019-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-51d53101edb548d5bfcae6feb9c2312e2022-12-21T19:24:45ZengFrontiers Media S.A.Frontiers in Neurology1664-22952019-06-011010.3389/fneur.2019.00675465444Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation MechanismAdrián Martín-Segura0Adrián Martín-Segura1Álvaro Casadomé-Perales2Pietro Fazzari3Pietro Fazzari4José Manuel Mas5Laura Artigas6Raquel Valls7Angel R. Nebreda8Angel R. Nebreda9Carlos G. Dotti10Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, SpainAlbert Einstein College of Medicine, Bronx, NY, United StatesDepartment of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, SpainDepartment of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, SpainCentro de Investigación Príncipe Felipe, Valencia, SpainAnaxomics Biotech, Barcelona, SpainAnaxomics Biotech, Barcelona, SpainAnaxomics Biotech, Barcelona, SpainInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainInstitució Catalana de Recerca i Estudis Avançats, Barcelona, SpainDepartment of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, SpainNumerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, high levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes.https://www.frontiersin.org/article/10.3389/fneur.2019.00675/fullcholesterolRTKsp38MAPKagingDUSP2 |
| spellingShingle | Adrián Martín-Segura Adrián Martín-Segura Álvaro Casadomé-Perales Pietro Fazzari Pietro Fazzari José Manuel Mas Laura Artigas Raquel Valls Angel R. Nebreda Angel R. Nebreda Carlos G. Dotti Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism Frontiers in Neurology cholesterol RTKs p38MAPK aging DUSP2 |
| title | Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism |
| title_full | Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism |
| title_fullStr | Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism |
| title_full_unstemmed | Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism |
| title_short | Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism |
| title_sort | aging increases hippocampal dusp2 by a membrane cholesterol loss mediated rtk p38mapk activation mechanism |
| topic | cholesterol RTKs p38MAPK aging DUSP2 |
| url | https://www.frontiersin.org/article/10.3389/fneur.2019.00675/full |
| work_keys_str_mv | AT adrianmartinsegura agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT adrianmartinsegura agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT alvarocasadomeperales agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT pietrofazzari agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT pietrofazzari agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT josemanuelmas agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT lauraartigas agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT raquelvalls agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT angelrnebreda agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT angelrnebreda agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism AT carlosgdotti agingincreaseshippocampaldusp2byamembranecholesterollossmediatedrtkp38mapkactivationmechanism |