Dataset Information

Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism.

ABSTRACT: 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.

SUBMITTER: Martin-Segura A

PROVIDER: S-EPMC6603139 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism.

Martín-Segura Adrián A Casadomé-Perales Álvaro Á Fazzari Pietro P Mas José Manuel JM Artigas Laura L Valls Raquel R Nebreda Angel R AR Dotti Carlos G CG

Frontiers in neurology 20190625

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 hippocampu ...[more]

PMID: 31293510

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Project description:Maintaining a normal cholesterol balance is crucial for the functioning of a healthy brain. Dysregulation in cholesterol metabolism and homeostasis in the brain have been correlated to various neurological disorders. The majority of previous studies in primary cultures focus on the role of cholesterol balance in neuronal development after polarity has been established. Here we have investigated how transient alteration of membrane lipids, specifically cholesterol, affects neuronal development and polarity in developing hippocampal neurons prior to polarity establishment, soon after initiation of neurite outgrowth. We observed that temporary cholesterol perturbation affects axonal and dendritic development differentially in an opposing manner. Transient membrane cholesterol deficiency increased neuronal population with a single neurite, simultaneously generating a second population of neurons with supernumerary axons. Brief replenishment of cholesterol immediately after cholesterol sequestering rescued neuronal development defects and restored polarity. The results showed a small window of cholesterol concentration to be complementing neurite outgrowth, polarity reestablishment, and in determining the normal neuronal morphology, emphasizing the critical role of precise membrane lipid balance in defining the neuronal architecture. Membrane cholesterol enhancement modified neurite outgrowth but did not significantly alter polarity. Cholesterol sequestering at later stages of development has shown to enhance neurite outgrowth, whereas distinct effects for neurite development and polarity were observed at early developmental stages, signifying the relevance of precise membrane cholesterol balance in altering neuronal physiology. Our results confirm cholesterol to be a key determinant for axo-dendritic specification and neuronal architecture and emphasize the possibility to reverse neuronal developmental defects caused by cholesterol deficiency by modulating membrane cholesterol during the early developmental stages.

Project description:BackgroundMuscle mitochondrial decline is associated with aging-related muscle weakness and insulin resistance. FoxO transcription factors are targets of insulin action and deletion of FoxOs improves mitochondrial function in diabetes. However, disruptions in proteostasis and autophagy are hallmarks of aging and the effect of chronic inhibition of FoxOs in aged muscle is unknown. This study investigated the role of FoxOs in regulating muscle strength and mitochondrial function with age.MethodsWe measured muscle strength, cross-sectional area, muscle fibre-type, markers of protein synthesis/degradation, central nuclei, glucose/insulin tolerance, and mitochondrial bioenergetics in 4.5-month (Young) and 22-24-month-old (Aged) muscle-specific FoxO1/3/4 triple KO (TKO) and littermate control (Ctrl) mice.ResultsLean mass was increased in Aged TKO compared with both Aged Ctrl and younger groups by 26-33% (P < 0.01). Muscle strength, measured by max force of tibialis anterior (TA) contraction, was 20% lower in Aged Ctrl compared with Young Ctrls (P < 0.01) but was not decreased in Aged TKOs. Increased muscle strength in Young and Aged TKO was associated with 18-48% increased muscle weights compared with Ctrls (P < 0.01). Muscle cross-sectional analysis of TA, soleus, and plantaris revealed increases in fibre size distribution and a 2.5-10-fold increase in central nuclei in Young and Aged TKO mice, without histologic signs of muscle damage. Age-dependent increases in Gadd45a and Ube4a expression as well accumulation of K48 polyubiquitinated proteins were observed in quad and TA but were prevented by FoxO deletion. Young and Aged TKO muscle showed minimal changes in autophagy flux and no accumulation of autophagosomes compared with Ctrl groups. Increased strength in Young and Aged TKO was associated with a 10-20% increase in muscle mitochondrial respiration using glutamate/malate/succinate compared with controls (P < 0.05). OXPHOS subunit expression and complex I activity were decreased 16-34% in Aged Ctrl compared with Young Ctrl but were prevented in Aged TKO. Both Aged Ctrl and Aged TKO showed impaired glucose tolerance by 33% compared to young groups (P < 0.05) indicating improved strength and mitochondrial respiration are not due to improved glycemia.ConclusionsFoxO deletion increases muscle strength even during aging. Deletion of FoxOs maintains muscle strength in part by mild suppression of atrophic pathways, including inhibition of Gadd45a and Ube4a expression, without accumulation of autophagosomes in muscle. Deletion of FoxOs also improved mitochondrial function by maintenance of OXPHOS in both young and aged TKO.

Dataset Information

Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism.

Publications

Aging Increases Hippocampal DUSP2 by a Membrane Cholesterol Loss-Mediated RTK/p38MAPK Activation Mechanism.

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