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

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

Author information

1
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
2
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
3
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
4
Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
5
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA; Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA. Electronic address: Brian.Kaspar@NationwideChildrens.org.

Abstract

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.

PMID:
24607225
PMCID:
PMC3978641
DOI:
10.1016/j.neuron.2014.01.013
[Indexed for MEDLINE]
Free PMC Article
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