title: Astroglial inhibition of NF-κB does not ameliorate disease onset and progression in a mouse model for amyotrophic lateral sclerosis (ALS).
abstract: Motor neuron death in amyotrophic lateral sclerosis (ALS) is considered a "non-cell autonomous" process, with astrocytes playing a critical role in disease progression. Glial cells are activated early in transgenic mice expressing mutant SOD1, suggesting that neuroinflammation has a relevant role in the cascade of events that trigger the death of motor neurons. An inflammatory cascade including COX2 expression, secretion of cytokines and release of NO from astrocytes may descend from activation of a NF-κB-mediated pathway observed in astrocytes from ALS patients and in experimental models. We have attempted rescue of transgenic mutant SOD1 mice through the inhibition of the NF-κB pathway selectively in astrocytes. Here we show that despite efficient inhibition of this major pathway, double transgenic mice expressing the mutant SOD1(G93A) ubiquitously and the dominant negative form of IκBα (IκBαAA) in astrocytes under control of the GFAP promoter show no benefit in terms of onset and progression of disease. Our data indicate that motor neuron death in ALS cannot be prevented by inhibition of a single inflammatory pathway because alternative pathways are activated in the presence of a persistent toxic stimulus.
authors: Department of Physiological, Biochemical and Cell Science, University of Sassari, Sassari, Italy. ccrosio@uniss.it
authors: Claudia
authors: C
authors: Crosio
authors: Cristiana
authors: C
authors: Valle
authors: Arianna
authors: A
authors: Casciati
authors: Ciro
authors: C
authors: Iaccarino
authors: Maria Teresa
authors: MT
authors: Carrì
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D016328:NF-kappa B; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase