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Prion diseases are transmissible neurodegenerative diseases caused by an infectious agent thought to be composed mainly of a host protein, the prion protein (PrP). The mechanisms of neurodegeneration prevailing in these diseases are not well understood. In the present study, we demonstrate that small PrP aggregates, called oligomers, cause the death of neurons in culture and after injection in vivo. On the contrary, larger PrP aggregates, visualized as fibrils by electron microscopy, do not cause the death of cultured neurons and are much less toxic than PrP oligomers in vivo. We propose that the PrP oligomers exert their toxicity by disturbing neuronal membranes, as well as by an excessive intracellular concentration leading to the generation of death signals (also called apoptotic signals) by the cell. Moreover, the use of antibodies recognizing a certain portion of the PrP oligomers could prevent neuronal death. This study assigns prion diseases to the same group of diseases as Alzheimer disease, in which protein oligomers constitute the major trigger of the neurodegenerative process, and suggests new possible neuroprotective approaches for therapeutic strategies.