Microglia Induce Motor Neuron Death via the Classical NF-[kappa]B Pathway in Amyotrophic Lateral Sclerosis

• Published in: Neuron (Cambridge, Mass.) Mass.), 2014-03, Vol.81 (5), p.1009
• Main Authors: Frakes, Ashley E, Ferraiuolo, Laura, Haidet-Phillips, Amanda M, Schmelzer, Leah, Braun, Lyndsey, Miranda, Carlos J, Ladner, Katherine J, Bevan, Adam K, Foust, Kevin D, Godbout, Jonathan P, Popovich, Phillip G, Guttridge, Denis C, Kaspar, Brian K
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Disease; Gene expression; Kinases; Laboratories; Mutation; Neurodegeneration; Phosphorylation; Rodents; Software; Studies
• ISSN: 0896-6273; 1097-4199
• 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.