Neuronal death is a pathological hallmark of prion diseases. Synthetic prion peptide PrP106-126 can convert PrP(C) into protease-resistant aggregates, which can cause neurotoxicity in vivo and in vitro. Various cell surface proteins can participate in the infection process of prions. p75(NTR) can interact with PrP106-126 and has a neurotoxic effect on neurons. However, for p75(NTR) lacking intrinsic catalytic activity domain in cytoplasm, p75(NTR) -associated signaling molecular and the signaling events in cytoplasm in p75(NTR)-mediated apoptosis responding to PrP106-126 remain still unknown. Thus p75(NTR) -associated NF-kappaB signaling pathway was investigated in this study. Herein PrP106-126-induced apoptosis in mouse neuroblastoma cell line N2a, PrP106-126 significantly up-regulated p75(NTR) expression on mRNA and protein levels. For the first time we found that PrP106-126 induced activation of NF-kappaB by Western blot assay, and blocking the interaction of p75(NTR) with PrP106-126 by p75(NTR) polyclonal antibody sc-6189 or pretreatment with inhibitor NF-kappaB SN50 reduced the activation of NF-kappaB and attenuated the apoptotic effect by PrP106-126. This study offers a possible interpretation that NF-kappaB signaling pathway was activated by the interaction of PrP106-126 with p75(NTR), and NF-kappaB activity showed the pro-apoptotic effect in PrP106-126-induced apoptosis in N2a cells. Involvement of NF-kappaB signaling pathway in p75(NTR)-mediated apoptosis may partially account for the PrP106-126-induced neurotoxicity in N2a cells.