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Updated: Jul 10, 2026
Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity
Published on: October 25, 2016
Microglia induce neurotoxicity via intraneuronal Zn(2+) release and a K(+) current surge
Megan E Knoch1, Karen A Hartnett, Hirokazu Hara
1Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Abstract:
Microglial cells are critical components of the injurious cascade in a large number of neurodegenerative diseases. However, the precise molecular mechanisms by which microglia mediate neuronal cell death have not been fully delineated. We report here that reactive species released from activated microglia induce the liberation of Zn(2+) from intracellular stores in cultured cortical neurons, with a subsequent enhancement in neuronal voltage-gated K(+) currents, two events that have been intimately linked to apoptosis. Both the intraneuronal Zn(2+) release and the K(+) current surge could be prevented by the NADPH oxidase inhibitor apocynin, the free radical scavenging mixture of superoxide dismutase and catalase, as well as by 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) chloride. The enhancement of K(+) currents was prevented by neuronal overexpression of metallothionein III or by expression of a dominant negative (DN) vector for the upstream mitogen-activated protein kinase apoptosis signal regulating kinase-1 (ASK-1). Importantly, neurons overexpressing metallothionein-III or transfected with DN vectors for ASK-1 or Kv2.1-encoded K(+) channels were resistant to microglial-induced toxicity. These results establish a direct link between microglial-generated oxygen and nitrogen reactive products and neuronal cell death mediated by intracellular Zn(2+) release and a surge in K(+) currents.
Insights
Activated microglia release reactive species that cause zinc (Zn2+) release and potassium (K+) current surges in neurons, leading to cell death in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglial cells play a key role in neurodegenerative disease pathogenesis.
- The exact molecular mechanisms of microglial-mediated neuronal death remain unclear.
Purpose of the Study:
- To elucidate the molecular pathways linking activated microglia to neuronal apoptosis.
- To investigate the role of reactive species, zinc (Zn2+), and potassium (K+) currents in microglial-induced neurotoxicity.
Main Methods:
- Utilized cultured cortical neurons and activated microglia.
- Assessed intracellular Zn2+ release and neuronal voltage-gated K+ currents.
- Employed inhibitors (apocynin, superoxide dismutase, catalase, porphyrinato iron(III) chloride) and genetic manipulations (metallothionein III overexpression, dominant-negative ASK-1 or Kv2.1 vectors).
Main Results:
- Microglial reactive species triggered intraneuronal Zn2+ release and enhanced K+ currents.
- These effects were blocked by NADPH oxidase inhibitors and free radical scavengers.
- Neuronal overexpression of metallothionein III or dominant-negative ASK-1/Kv2.1 conferred resistance to microglial toxicity.
Conclusions:
- Established a direct link between microglial-derived reactive oxygen and nitrogen species and neuronal death.
- Demonstrated that intracellular Zn2+ release and K+ current surges are critical mediators of this toxicity.
- Identified potential therapeutic targets (ASK-1, Kv2.1, metallothionein III) for neurodegenerative diseases.
