Related Experiment Video
Updated: May 2, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis
Ashley E Frakes1, Laura Ferraiuolo2, Amanda M Haidet-Phillips2
1Center 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.
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.
Insights
In amyotrophic lateral sclerosis (ALS), inhibiting nuclear factor-kappa B (NF-κB) in microglia, but not astrocytes, rescues motor neurons. This suggests targeting microglial NF-κB is a potential therapeutic strategy for ALS.
Area of Science:
- Neuroscience
- Immunology
- Neuroinflammation
Background:
- Neuroinflammation is a key feature of amyotrophic lateral sclerosis (ALS).
- Nuclear factor-kappa B (NF-κB), a central regulator of inflammation, is elevated in ALS spinal cords.
Purpose of the Study:
- To investigate the role of NF-κB signaling in microglia and astrocytes in ALS pathogenesis.
- To determine if selective inhibition of NF-κB in different cell types can protect motor neurons.
Main Methods:
- Utilized mouse models of ALS (SOD1-G93A) and wild-type mice.
- Manipulated NF-κB signaling selectively in astrocytes and microglia.
- Assessed motor neuron survival in vitro and in vivo.
- Evaluated microglial activation and gliosis.
Main Results:
- Selective NF-κB inhibition in ALS astrocytes did not prevent motor neuron death.
- Deleting NF-κB signaling in microglia rescued motor neurons from microglial-mediated death in vitro.
- Targeting microglial NF-κB extended survival in ALS mice by reducing proinflammatory microglial activation.
- Constitutive activation of NF-κB in wild-type microglia induced gliosis and motor neuron death.
Conclusions:
- Microglia play a critical role in motor neuron death in ALS through NF-κB signaling.
- Targeting microglial NF-κB activation represents a promising therapeutic strategy for ALS.
- This approach may also benefit other neurodegenerative diseases involving microglial activation.
