Microglia induce neurotoxicity via intraneuronal Zn²⁺ release and a K⁺ current surge

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.

Convergent Ca 2+ and Zn 2+ signaling regulates apoptotic Kv2.1 K + currents

“…Next, to determine whether inhibition of CaMKII was neuroprotective, we transfected neurons with a plasmid encoding CaMKIIK42R (or empty vector) in addition to a luciferase-expressing plasmid used to assess viability in transfected cells (54). Neurons were later exposed to activated rat microglia (55), which we showed to be a powerful inducer of Zn 2+ -dependent, Kv2.1-mediated injury via peroxynitrite production (56). We observed that neurons expressing CaMKIIK42R were significantly protected from microglia toxicity compared with vector-expressing cells (Fig.…”

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

“…When stimulated during brain injury, the overactivation and dysregulation of microglia can compound neuronal damage by releasing neurotoxic cytokines, matrix metalloproteinases, and NO and superoxide (O (52). Further, microglia-derived reactive oxygen and nitrogen species (ROS and RNS) triggered the well-characterized apoptotic signalregulating kinase-1 (ASK1)=p38-dependent, Kv2.1-mediated K þ current surge (52).…”

“…Further, microglia-derived reactive oxygen and nitrogen species (ROS and RNS) triggered the well-characterized apoptotic signalregulating kinase-1 (ASK1)=p38-dependent, Kv2.1-mediated K þ current surge (52). When these studies were repeated in neurons overexpressing MT III, thereby chelating free Zn 2þ , the K þ current surge and neuronal cell death were markedly reduced (52). Thus, microglial activation can lead to a neuronal free Zn 2þ rise and Zn 2þ -dependent neuronal cell death.…”

Newly Synthesized ‘Hidabeni’ Chalcone Derivatives Potently Suppress LPS-Induced NO Production <i>via</i> Inhibition of STAT1, but Not NF-κB, JNK, and p38, Pathways in Microglia

“…Activated microglia produce inflammatory mediators including nitric oxide (NO), superoxide, and proinflammatory cytokines, leading to a robust neuroinflammatory response. 4,5) NO produced by inducible NO synthase (iNOS) rapidly reacts with superoxide to form a highly toxic product, peroxynitrite. This product has been shown to exaggerate neuropathological injury.…”