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

Neuron 2014

Frakes, Ashley E. and Ferraiuolo, Laura and Haidet-Phillips, Amanda M. and Schmelzer, Leah and Braun, Lyndsey and Miranda, Carlos J. and Ladner, Katherine J. and Bevan, Adam K. and Foust, Kevin D. and Godbout, Jonathan P. and Popovich, Phillip G. and Guttridge, Denis C. and Kaspar, Brian K.

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.

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