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Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity
Dafina M Angelova1, David R Brown2
1Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK. D.M.Angelova@bath.ac.uk.
Biomolecules
|August 4, 2018
Summary
Aging brains feature dystrophic microglia, which can impair neuroprotection. This study models these aged microglia to investigate their role in α-synuclein diseases, revealing their impact on protein aggregation.
Area of Science:
- Neuroscience
- Aging Research
- Cell Biology
Background:
- Aging is a primary risk factor for neurodegenerative diseases.
- Microglia, the brain's immune cells, adopt a less responsive, dystrophic phenotype with age.
- Current models often overlook age-related microglial changes.
Purpose of the Study:
- To develop an in vitro model of aged, dystrophic microglia.
- To investigate the influence of these aged microglia on α-synuclein, a key protein in neurodegeneration.
- To explore the molecular mechanisms by which dystrophic microglia affect α-synuclein.
Main Methods:
- Cultured mouse microglia in high iron concentrations to induce a senescent, dystrophic phenotype.
- Characterized dystrophic microglia by measuring iron storage, protein expression (ferritin, Kv1.3), reactive oxygen species, and cytokine release.
- Applied conditioned medium from dystrophic microglia to α-synuclein studies.
Main Results:
- High iron induced microglial characteristics of dystrophic cells, including increased ferritin and Kv1.3 expression.
- Conditioned medium from dystrophic microglia enhanced α-synuclein transcription and expression via tumor necrosis factor alpha (TNFα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling.
- Dystrophic microglia-derived factors reduced α-synuclein tetramer formation and ferrireductase activity, while increasing α-synuclein aggregation.
Conclusions:
- Successfully developed an in vitro model for aged, dystrophic microglia.
- Dystrophic microglia release factors, such as TNFα, that significantly influence α-synuclein behavior.
- These findings suggest a crucial role for aged microglia in the pathogenesis of α-synuclein-related neurodegenerative diseases.
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