Susceptibility of Transgenic mice expressing chimeric sheep, bovine and human PrP genes to sheep scrapie

The use of Transgenic (Tg) mice expressing chimeric sheep/mouse (Sh/Mo) prion protein (PrP) and chimeric bovine/mouse (Bo/Mo) PrP genes was evaluated as a sheep scrapie model. We also investigated the potential for the transmission of sheep scrapie to a human/mouse (Hu/Mo) PrP Tg mouse line. The Sh/Mo PrP and Bo/Mo PrP Tg Prnp^+/+ or Prnp^0/0 mouse lines were inoculated intracerebrally with brain homogenates from three sheep with natural scrapie (KU, Y5 or S2). Incubation periods were slightly shorter in Sh/Mo PrP Tg Prnp^+/+, than in non-Tg mice inoculated with KU brain homogenate. In contrast, the incubation period was significantly prolonged (p<0.05) in Bo/Mo PrP Tg Prnp^+/+ mice inoculated with KU brain homogenate. The incubation period was significantly longer in all Tg Prnp^+/+ and Prnp^0/0, than in non-Tg mice (p<0.01) inoculated withY5 brain homogenate. None of the Tg Prnp^0/0 mice inoculated with S2 brain homogenate developed clinical signs and PrP^Sc was undetectable in their brains. These results suggested that expression of the Sh/Mo PrP or Bo/Mo PrP transgenes does not confer susceptibility to sheep prions upon mice, and thus none of the Tg mouse lines could be a suitable model of sheep scrapie. Hu/Mo PrP Tg Prnp^0/0 mice inoculated with natural and experimental scrapie or mouse prions did not develop clinical signs of scrapie and PrP ^Sc was undetectable. These results suggested that neither sheep nor mouse strains of scrapie are highly transmissible to humans.