The prion diseases are neurodegenerative disorders characterized by the conversion of the PrPc (normal cellular prion) to the PrPsc (misfolded isoform) The accumulation of PrPsc within the central nervous system (CNS) leads to neurocytotoxicity by increasing oxidative stress In addition many neurodegenerative disorders including prion Parkinson s and Alzheimer s diseases may be regulated by cholesterol homeostasis The effects of cholesterol balance on prion protein-mediated neurotoxicity and ROS (reactive oxygen species) generation were the focus of this study Cholesterol treatment inhibited PrP (106-126)-induced neuronal cell death and ROS generation in SH-SY5Y neuroblastoma cells In addition the PrP (106-126)mediated increase of p53 p-p38 p-ERK and the decrease of Bcl-2 were blocked by cholesterol treatment These results indicated that cellular cholesterol enrichment is a key regulator of PrP-106-126-mediated oxidative stress and neurotoxicity Taken together the results of this study suggest that modulation of cellular cholesterol appears to prevent the neuronal cell death caused by prion peptides (C) 2010 Elsevier Inc All rights reserved