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Updated: Apr 12, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
P2X7 receptor is critical in α-synuclein--mediated microglial NADPH oxidase activation
Tianfang Jiang1, Jake Hoekstra2, Xin Heng1
1Department of Neurology & Institute of Neurology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Activated microglia are commonly observed in individuals with neurodegenerative disorders, including Parkinson's disease (PD) and are believed to contribute to neuronal death. This process occurs at least due partially to nicotinamide adenine dinucleotide phosphate oxidase (PHOX) activation, which leads to the production of superoxide and oxidative stress. α-Synuclein (α-Syn), a key protein implicated in PD pathogenesis, can activate microglia, contributing to death of dopaminergic neurons. Here, microglial cells (BV2) and primary cultured microglia were used to study the role that the purinergic receptor P2X7 plays in recognizing α-Syn and promoting PHOX activation. We demonstrate that both wild type and A53T mutant α-Syn readily activate PHOX, with the A53T form producing more rapid and sustained effects,that is, oxidative stress and cellular injuries. Furthermore, this process involves the activation of phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B) pathway. Thus, it is concluded that stimulation of the microglial P2X7 receptor by extracellular α-Syn, with PI3K/AKT activation and increased oxidative stress, could be an important mechanism and a potential therapeutic target for PD.
Insights
Activated microglia contribute to Parkinson's disease (PD) neurodegeneration. Extracellular alpha-synuclein (α-Syn) activates microglial P2X7 receptors, triggering oxidative stress and neuronal damage, presenting a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Activated microglia are implicated in neurodegenerative disorders like Parkinson's disease (PD).
- Nicotinamide adenine dinucleotide phosphate oxidase (PHOX) activation in microglia leads to oxidative stress and neuronal death.
- Alpha-synuclein (α-Syn) is a key protein in PD pathogenesis that activates microglia.
Purpose of the Study:
- To investigate the role of the purinergic receptor P2X7 in microglial recognition of α-Syn.
- To determine how P2X7 activation promotes PHOX activation and subsequent oxidative stress.
- To explore the involvement of the PI3K/AKT pathway in this process.
Main Methods:
- Utilized BV2 and primary cultured microglia.
- Stimulated microglia with wild-type and A53T mutant α-Syn.
- Assessed PHOX activation, oxidative stress markers, and PI3K/AKT pathway activation.
Main Results:
- Both wild-type and A53T α-Syn activated PHOX, leading to oxidative stress and cellular injury.
- The A53T mutant α-Syn induced more rapid and sustained PHOX activation.
- Activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway was observed.
Conclusions:
- Extracellular α-Syn stimulation of microglial P2X7 receptors is a key mechanism in PD pathogenesis.
- This pathway involves PI3K/AKT activation and increased oxidative stress.
- Microglial P2X7 receptor represents a potential therapeutic target for Parkinson's disease.
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