期刊
NEURON
卷 81, 期 5, 页码 1009-1023出版社
CELL PRESS
DOI: 10.1016/j.neuron.2014.01.013
关键词
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资金
- US National Institutes of Health (NIH) [R01 NS644912]
- Project A.L.S.
- Packard Center for ALS Research (P2ALS)
- Helping Link Foundation
- NINDS [T32NS077984]
- Marie Curie Fellowship
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.
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