Copper induces microglia-mediated neuroinflammation through ROS/NF-κB pathway and mitophagy disorder

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Epidemiological studies link copper exposure to increased Parkinson disease (PD) risk.
• Microglia-mediated neuroinflammation is a key factor in PD pathogenesis.

Purpose of the Study:

• To investigate microglial activation and neuroinflammation in copper neurotoxicity.
• To elucidate the mechanism of copper-induced microglial activation.

Main Methods:

• Examined inflammatory changes, microglial activation, dopaminergic neuron loss, and alpha-synuclein aggregation in mouse brain tissue.
• Assessed copper-induced inflammatory activation, reactive oxygen species (ROS) production, and NF-κB pathway activation in BV2 cells.
• Analyzed mitochondrial function, mitophagy markers (Parkin, PINK1, P62, LC3B), and pyroptosis-related proteins (NLRP3/caspase1/GSDMD axis).

Main Results:

• Copper exposure activated microglia and increased ROS levels, activating the NF-κB pathway in BV2 cells.
• Sustained copper accumulation impaired mitochondrial function, disrupted mitophagy, and upregulated the NLRP3/caspase1/GSDMD axis.
• Redox agents, NF-κB inhibitors, and mitophagy inducers mitigated inflammatory factor release.

Conclusions:

• Copper exposure activates microglia, leading to neuroinflammation and dopaminergic neuron pyroptosis.
• The mechanism involves early ROS/NF-κB pathway activation and subsequent mitophagy disorder.
• These findings highlight copper's role in PD pathogenesis via microglial-mediated neuroinflammation.