Microglia Induce Motor Neuron Death via the Classical NF-κB Pathway in Amyotrophic Lateral Sclerosis

Neuroinflammation is one of the most striking hallmarks of amyotrophic lateral sclerosis (ALS). Nuclear factor-kappa B (NF-kappa B), a master regulator of inflammation, is upregulated in spinal cords of ALS patients and SOD1-G93Amice. In this study, we show that selective NF-kappa B inhibition in ALS astrocytes is not sufficient to rescue motor neuron (MN) death. However, the localization of NF-kappa B activity and subsequent deletion of NF-kappa B 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-kappa B 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.