Alteration of NF-kappa B activity leads to mitochondrial apoptosis after infection with pathological prion protein

Nuclear factor kappa B (NF-kB) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, prolifera- tion and regulation of apoptosis. In the central nervous system activated NF-kB plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-kB is well characterized, there is poor knowledge on the role of NF-kB in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-kB activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-kB after prion infection of Nfkb1–/– and Bcl3–/–, Nfkb2–/–mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-kB2- and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-kB activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis.