Development of transgenic mouse models expressing heterologous
prion protein (PrP) has facilitated and advanced in vivo studies of
prion diseases affecting humans and animals. Here, novel transgenic mouse lines expressing a chimaeric murine/ovine (Mu/Ov) PrP transgene, including
amino acid residues
alanine,
histidine and
glutamine at ovine polymorphic
codons 136, 154 and 171 (A136H154Q171), were generated to provide a means of assessing the susceptibility of the ovine AHQ allele to ruminant
prion diseases in an in vivo model. Transmission studies showed that the highest level of transgene overexpression, in Tg(Mu/OvPrP(AHQ))
EM16 (
EM16) mice, conferred high susceptibility to ruminant
prions. Highly efficient primary transmission of atypical
scrapie from sheep was shown, irrespective of donor sheep PrP genotype, with mean incubation periods (IPs) of 154–178 days post-inoculation (p.i.), 100% disease penetrance and early Western blot detection of
protease-resistant fragments (
PrP(res)) of the disease-associated
isoform, PrP(Sc), in
EM16 brain from 110 days p.i. onwards.
EM16 mice were also highly susceptible to classical
scrapie and
bovine spongiform encephalopathy (BSE), with mean IPs 320 and 246 days faster, respectively, than WT mice. Primary passage of atypical
scrapie, classical
scrapie and BSE showed that the
PrP(res) profiles associated with disease in the natural host were faithfully maintained in
EM16 mice, and were distinguishable based on molecular masses, antibody reactivities and glycoform percentages. Immunohistochemistry was used to confirm PrP(Sc) deposition in brain sections from terminal phase
transmissible spongiform encephalopathy-challenged
EM16 mice. The findings indicate that
EM16 mice represent a suitable bioassay model for detection of atypical
scrapie infectivity and offer the prospect of differentiation of ruminant
prions.