Prion protein-overexpressing cells show altered response to a neurotoxic prion protein peptide

A peptide fragment of the prion protein, PrP106-126 is toxic to neuronal cells in culture. This toxicity is dependent on neuronal expression of the prion protein (PrPc) and also the presence of microglia. The role of expression of the PrPc in neurotoxicity of this peptide was investigated using mice that overexpress the prion protein. Cells derived from two different strains of PrPc-overexpressing mice were used (Tg20 and Tg35). PrP106-126 was more toxic to Tg35 cerebellar cells than wild-type or Tg20 cells. This increased toxicity required the presence of microglia. Analysis of microglia derived from wild-type and PrPc-overexpressing cells showed that Tg35 microglia were more easily activated than wild-type microglia, were more easily stimulated to proliferate by astrocytes, and had a higher level of PrPc expression. This may explain the increased PrP106-126 toxicity to Tg35 PrPc-overexpressing cerebellar cells. These results suggest that the toxicity of PrP106-126 may depend on the level of expression of PrPc by microglia as well as by neurones.