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Prion Protein Aggregation and Neurotoxicity in Cortical Neurons

Abstract:  Prion diseases are degenerative disorders of the central nervous system characterized by cerebral protein aggregation and deposition. A cellular glycoprotein, PrPC is converted in an altered isoform, PrPSc, that accumulates in the brain, and is believed to be responsible for the neuronal loss observed in prion diseases. The synthetic peptide PrP106‐126 shares many characteristics with PrPSc and is largely used to explore the toxic mechanisms underlying prion diseases. In this article we analyzed the neurotoxic effects of PrP106‐126 in primary rat brain cortical neurons, correlating these results with the presence of amyloid plaques in cultures. Incubation of cells with PrP106‐126, 25 μM, for 2 days did not significantly decrease neuronal viability, although we have observed an increase of basal intracellular calcium levels, reactive oxygen species (ROS) formation, and lipid peroxidation. The presence of congophylic and thioflavin S‐amyloid‐positive plaques in cortical cultures was only observed after a 5‐day‐treatment period, correlating with a significant decrease of neuronal viability, as assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) leakage. The data obtained support the idea that PrP106‐126 aggregates in vitro and that the aggregation state is important for its neurotoxicity but also suggest that this synthetic peptide, even when is not aggregated invitro, can compromise cell homeostasis.