In this work we have investigated the molecular basis of the neuronal damage induced by the prion peptide by searching for a surface receptor, whose activation could be the first step of a cascade of events responsible for cell death. By using a human neuroblastoma cell line lacking all the neurotrophin receptors and derived clones expressing the full-length or truncated forms of the low-affinity neurotrophin receptor (p75NTR), we have been able to demonstrate that the neuronal death induced by the prion protein fragment PrP106-126 is an active process mediated by a) the binding of the peptide to the extra-cellular region of p75NTR, (b) the signalling function of the intra-cytoplasmic region of the receptor, and c) the activation of caspase-8 and the production of oxidant species.