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Acute Stress, Induced by IFNγ + Aβ, and Chronic Stress, Induced by Age, Affect Microglia in a Sex-Specific Manner
Virginia Mela1,2, Aline Sayd Gaban3, Paul Marie Shatz3
1Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Dublin 2, Ireland. virginiamelarivas@gmail.com.
Abstract:
Microglial phenotype changes in the aged brain, and also in neurodegenerative diseases, and it is generally accepted that these changes at least contribute to the inflammation that can have detrimental effects on brain health. Accumulating data have determined that there are multiple microglial activation states with consistent findings indicating that with stressors including age, a switch towards an inflammatory phenotype occurs. Among the changes that accompany this is a change in metabolism, whereby glycolysis is increased in microglia. Here, we asked whether sex impacted on the response of microglia to two stressors, interferon-γ + amyloid-β (IFNγ + Aβ) and age. The data show that IFNγ + Aβ triggered cells from female mice to adopt a glycolytic phenotype. Metabolism was also altered with age; microglia from aged male mice responded by increasing oxidative phosphorylation, and microglial motility was preserved, contrasting with microglia from female mice where motility was compromised. We conclude that sex is a significant variable in the responses of microglia to stressors.
Insights
Sex significantly influences microglial responses to brain stressors. Female microglia adopt a glycolytic phenotype with inflammation, while aged male microglia increase oxidative phosphorylation, preserving motility.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial phenotype shifts in aging and neurodegeneration contribute to detrimental brain inflammation.
- Microglia exhibit multiple activation states, often switching to an inflammatory phenotype under stress, including aging.
- Metabolic changes, such as increased glycolysis, accompany these microglial inflammatory responses.
Purpose of the Study:
- To investigate the impact of biological sex on microglial responses to specific stressors.
- To compare microglial metabolic and functional changes induced by interferon-gamma plus amyloid-beta (IFNγ + Aβ) and aging in male versus female mice.
Main Methods:
- Primary microglia cultures were treated with IFNγ + Aβ to simulate inflammatory conditions.
- Microglial metabolism was assessed by measuring glycolysis and oxidative phosphorylation.
- Microglial motility was evaluated in aged male and female mice.
Main Results:
- IFNγ + Aβ treatment induced a glycolytic phenotype in microglia from female mice.
- Microglia from aged male mice showed increased oxidative phosphorylation and preserved motility.
- Microglia from aged female mice exhibited compromised motility.
Conclusions:
- Biological sex is a critical variable modulating microglial responses to inflammatory and age-related stressors.
- Sex-specific alterations in microglial metabolism and function have implications for brain health in aging and disease.
- Understanding these sex differences is crucial for developing targeted neuroprotective strategies.
