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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Prostaglandin E2 receptor subtype 2 (EP2) regulates microglial activation and associated neurotoxicity induced by
Jinghua Jin1, Feng-Shiun Shie, Jun Liu
1Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA. jinj@u.washington.edu <jinj@u.washington.edu>
Background:
The pathogenesis of idiopathic Parkinson's disease (PD) remains elusive, although evidence has suggested that neuroinflammation characterized by activation of resident microglia in the brain may contribute significantly to neurodegeneration in PD. It has been demonstrated that aggregated alpha-synuclein potently activates microglia and causes neurotoxicity. However, the mechanisms by which aggregated alpha-synuclein activates microglia are not understood fully.
Methods:
We investigated the role of prostaglandin E2 receptor subtype 2 (EP2) in alpha-synuclein aggregation-induced microglial activation using ex vivo, in vivo and in vitro experimental systems.
Results:
Results demonstrated that ablation of EP2(EP2-/-) significantly enhanced microglia-mediated ex vivo clearance of alpha-synuclein aggregates (from mesocortex of Lewy body disease patients) while significantly attenuating neurotoxicity and extent of alpha-synuclein aggregation in mice treated with a parkinsonian toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Furthermore, we report that reduced neurotoxicity by EP2-/- microglia could be attributed to suppressed translocation of a critical cytoplasmic subunit (p47-phox) of NADPH oxidase (PHOX) to the membranous compartment after exposure to aggregated alpha-synuclein.
Conclusion:
Thus, it appears that microglial EP2 plays a critical role in alpha-synuclein-mediated neurotoxicity.
Insights
Microglial EP2 receptor is critical in Parkinson's disease pathogenesis. Inhibiting EP2 enhances alpha-synuclein clearance and reduces neurotoxicity, offering a potential therapeutic target for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Parkinson's disease (PD) pathogenesis is unclear, but neuroinflammation involving microglia activation contributes to neurodegeneration.
- Aggregated alpha-synuclein activates microglia and causes neurotoxicity, yet the precise mechanisms remain poorly understood.
Purpose of the Study:
- To investigate the role of prostaglandin E2 receptor subtype 2 (EP2) in microglial activation induced by aggregated alpha-synuclein.
Main Methods:
- Utilized ex vivo, in vivo, and in vitro experimental models.
- Examined the impact of EP2 ablation (EP2-/-) on alpha-synuclein aggregate clearance and neurotoxicity.
Main Results:
- EP2 deficiency enhanced microglia-mediated clearance of alpha-synuclein aggregates from human brain tissue.
- EP2 knockout attenuated neurotoxicity and alpha-synuclein aggregation in a mouse model of Parkinson's disease.
- Reduced neurotoxicity in EP2 knockout microglia was linked to suppressed p47-phox translocation in NADPH oxidase.
Conclusions:
- Microglial EP2 receptor plays a crucial role in alpha-synuclein-mediated neurotoxicity.
- Targeting microglial EP2 may offer a novel therapeutic strategy for Parkinson's disease.
