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

By Ashley E. Frakes, L. Ferraiuolo, Amanda M. Haidet-Phillips, Leah Schmelzer, Lyndsey Braun, Carlos J. Miranda, K. Ladner, A. Bevan, K. Foust, Jonathan P. Godbout and 3 more. Neuron, 2014

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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 pro-inflammatory 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.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/69fd2c2c65b1954c85c57369a8939a8e2ecc21ec

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In Neurology

Citations in the corpus

Reactive Astrocytes: Production, Function, and Therapeutic Potential. (2017, background): “Similarly, NFkB-GFP reporter mice crossed with Sod1G93A ALS mice showmore robust activation in microglia cells than in astrocytes, but again astrocyte reactivity was only assessed via GFAP immunoreactivity (Frakes et al., 2014).”