NF-kB Activation in Microglia Induces Motor Neuron Death in Amyotrophic lateral sclerosis
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Date
2013-03
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Abstract
ALS is a fatal neurodegenerative disease that affects motor neurons (MNs) resulting in severe muscle atrophy and paralysis. Despite the fact that about 5,600 people are diagnosed with ALS in the US each year, there is no cure. One of the most striking pathological hallmarks observed in patients and rodent models of ALS is neuroinflammation, characterized by activation of microglia, the resident immune cells of the central nervous system. Genetic approaches to globally eliminate single inflammatory genes in ALS mouse models have largely failed, highlighting the complexity of this inflammatory process. Nuclear Factor-kappa B (NF-κB) regulates many pro-inflammatory mediators found in areas of MN death in ALS, and this pathway is activated in the spinal cords of ALS patients. Therefore, the purpose of this study is to determine the role of NF-κB, a master regulator of inflammation, in ALS. By immunoblot and immunohistochemical analyses, we determined NF-kB activation increases with disease progression in ALS mice and occurs predominantly in microglia. To determine the role of NF-kB activation in microglial-mediated MN death, we utilized an in vitro co-culture model in which 61% of MNs die when co-cultured with ALS microglia after 72 hours. NF-kB inhibition in ALS microglia fully rescued MNs from microglial-mediated death in vitro. Remarkably, conditional inhibition of NF-kB in microglia in vivo extends survival in the ALS mice by delaying disease progression by 51%, one of the longest extensions reported in this severe model. NF-kB inhibition in microglia leads to marked reduction in prototypic inflammatory markers such as CD68, CD86 and iNOS, suggesting that NF-kB regulates microglial conversion to a pro-inflammatory, neurotoxic state in ALS. Furthermore, we show that constitutive activation of NF-kB selectively in microglia in wild-type mice promoted a similar microglial activation state observed in ALS mice. Strikingly, microglia isolated from these constitutively active NF-kB mice rapidly induced 48% MN death in vitro. These data provide a cellular and molecular mechanism by which microglia induce MN death in ALS and suggest a novel therapeutic target to modulate microglial activation and slow the progression of ALS and other neurodegenerative diseases by which microglial activation plays a role.
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Professional Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Amyotrophic Lateral Sclerosis, Microglia, Neurodegeneration, Motor Neuron