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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and
Aedín M Minogue1, Raasay S Jones1, Ronan J Kelly1
1Institute of Neuroscience, Trinity College, Dublin, Ireland.
Abstract:
Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse model of Alzheimer's disease and to delineate differences between normal aging and those associated with disease pathology. A proinflammatory profile, characterized by the upregulation of markers of classical activation, was evident in APPswe/PS1dE9 mice, associated with increased interferon-γ (IFNγ) concentration and dysregulation of mechanisms designed to limit the proinflammatory response. The data indicate that microglia are not less active with age but alter their phenotype; indeed, changes observed in the deactivation state appear to relate to aging rather than disease pathology. We hypothesize that disruption of the blood-brain barrier, in tandem with an enhanced chemokine profile, permits the infiltration of immune cells serving to reinforce classical activation of microglia through their enhanced responsiveness to IFNγ.
Insights
Aging brains exhibit heightened inflammation, with microglia altering their function rather than declining. This study reveals disease-specific inflammatory profiles in Alzheimer's models, distinct from normal aging processes.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Aging impairs brain inflammatory processes, potentially leading to neurodegeneration.
- Microglia dysfunction with age may compromise neuroprotection.
- Understanding age-related inflammation is crucial for neurodegenerative disease research.
Purpose of the Study:
- Characterize inflammatory changes in an Alzheimer's disease mouse model.
- Differentiate between normal aging and disease-associated inflammatory changes.
- Investigate microglial activation states in aging and Alzheimer's disease.
Main Methods:
- Utilized APPswe/PS1dE9 mouse model for Alzheimer's disease.
- Analyzed inflammatory markers and cytokine concentrations (e.g., interferon-γ).
- Assessed microglial activation and deactivation states.
Main Results:
- APPswe/PS1dE9 mice displayed a proinflammatory profile with upregulated classical activation markers.
- Increased interferon-γ (IFNγ) concentration and dysregulated anti-inflammatory mechanisms were observed.
- Changes in microglial deactivation states were linked to aging, not solely disease pathology.
Conclusions:
- Microglia alter their phenotype with age, not simply become less active.
- Aging, rather than Alzheimer's pathology, significantly impacts microglial deactivation.
- Blood-brain barrier disruption and chemokine profiles may drive immune cell infiltration and microglial activation in disease.
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