Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis

Neuron. 2014 Mar 5;81(5):1009-1023. doi: 10.1016/j.neuron.2014.01.013.


Neuroinflammation is one of the most striking hallmarks of amyotrophic lateral sclerosis (ALS). Nuclear factor-kappa B (NF-κB), a master regulator of inflammation, is upregulated in spinal cords of ALS patients and SOD1-G93A mice. In this study, we show that selective NF-κB inhibition in ALS astrocytes is not sufficient to rescue motor neuron (MN) death. However, the localization of NF-κB activity and subsequent deletion of NF-κB signaling in microglia rescued MNs from microglial-mediated death in vitro and extended survival in ALS mice by impairing proinflammatory microglial activation. Conversely, constitutive activation of NF-κB selectively in wild-type microglia induced gliosis and MN death in vitro and in vivo. Taken together, these data provide a mechanism by which microglia induce MN death in ALS and suggest a novel therapeutic target that can be modulated to slow the progression of ALS and possibly other neurodegenerative diseases by which microglial activation plays a role.

Publication types

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

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Animals, Newborn
  • Astrocytes / cytology
  • Astrocytes / metabolism
  • Cell Communication / physiology
  • Cell Death / physiology*
  • Coculture Techniques
  • Disease Models, Animal
  • Female
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
  • Microglia / cytology*
  • Microglia / metabolism
  • Motor Neurons / cytology*
  • Motor Neurons / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Primary Cell Culture
  • Signal Transduction / physiology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1


  • NF-kappa B
  • SOD1 G93A protein
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1