Neuron
Volume 81, Issue 5, 5 March 2014, Pages 1009-1023
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Article
Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis

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Highlights

  • NF-κB is activated in ALS, predominantly in microglia

  • Inhibition of microglial NF-κB delays disease progression by 47% in SOD1-G93A mice

  • Inhibition of NF-κB dampens proinflammatory microglial activation

  • Constitutive activation of microglial NF-κB induces pathological hallmarks of ALS

Summary

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.

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Present address: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA