Forebrain-Specific Neuronal Inhibition of Nuclear Factor-κB Activity Leads to Loss of Neuroprotection

Abstract

The transcription factor Rel/nuclear factor (NF)-κB is known for its fundamental role in regulating immune and inflammatory responses. In the brain, constitutive NF-κB activity has been detected exclusively in neurons, and a large diversity of stimuli have been reported to induce NF-κB activity. Yet the function of this transcription factor in the nervous system remains unclear, and its role in neuroprotection or neurodegeneration is open to debate. Recently it was suggested that κB-driven gene expression in neurons is controlled by Sp1-like factors. To clarify such controversy, we have characterized here a novel mouse model in which the entire NF-κ B-dependent transcriptional response is abolished in the forebrain. Calcium-calmodulin-dependent kinase II α promoter-driven tetracycline transactivator was used for regulated expression of a transdominant negative mutant of inhibitor κBα (super-repressor) together with a green fluorescent protein tracer. Inhibition of expression of a κB-dependent lacZ transgene was shown in triple transgenic mice, which correlated with the loss of κB-specific DNA binding. In transgenic organotypic hippocampal slice cultures, expression of the super-repressor led to strong cell death after neurotoxic insults. These data demonstrate for the first time that neuron-restricted ablation of NF-κB-driven gene expression increases neurodegeneration. This might lead to the path for new treatments of neurodegenerative diseases.