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Prion Protein Aggregation and Neurotoxicity in Cortical Neurons

2007; Wiley; Volume: 1096; Issue: 1 Linguagem: Inglês

10.1196/annals.1397.088

1749-6632

Joana Barbosa Melo, Paula Agostinho, Catarina R. Oliveira,

Neurological diseases and metabolism

Abstract : Prion diseases are degenerative disorders of the central nervous system characterized by cerebral protein aggregation and deposition. A cellular glycoprotein, PrP C is converted in an altered isoform, PrP Sc , that accumulates in the brain, and is believed to be responsible for the neuronal loss observed in prion diseases. The synthetic peptide PrP 106‐126 shares many characteristics with PrP Sc and is largely used to explore the toxic mechanisms underlying prion diseases. In this article we analyzed the neurotoxic effects of PrP 106‐126 in primary rat brain cortical neurons, correlating these results with the presence of amyloid plaques in cultures. Incubation of cells with PrP 106‐126 , 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 PrP 106‐126 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 in vitro , can compromise cell homeostasis.