Microglia induce neurotoxicity via intraneuronal Zn(2+) release and a K(+) current surge

Glia. 2008 Jan 1;56(1):89-96. doi: 10.1002/glia.20592.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / physiology
  • Cerebral Cortex / cytology
  • Cerebral Cortex / physiology
  • Coculture Techniques
  • Electrophysiology
  • Female
  • Immunohistochemistry
  • Ion Channel Gating / physiology
  • Ion Channels / drug effects
  • Ion Channels / physiology
  • Luciferases / genetics
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / physiology
  • Microglia / pathology
  • Microglia / physiology*
  • Neurodegenerative Diseases / pathology*
  • Neurons / pathology*
  • Potassium Channels / drug effects
  • Potassium Channels / physiology*
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Shab Potassium Channels / genetics
  • Shab Potassium Channels / physiology
  • Signal Transduction / physiology
  • Transfection
  • Zinc / metabolism*

Substances

  • Ion Channels
  • Kcnb1 protein, rat
  • Potassium Channels
  • Shab Potassium Channels
  • Luciferases
  • MAP Kinase Kinase Kinase 5
  • Zinc