Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system

Mice devoid of PrP^C (Prnp^o/o) are resistant to scrapie and do not allow propagation of the infectious agent (prion). PrP^C-expressing neuroectodermal tissue grafted into Prnp^o/o brains but not the surrounding tissue consistently exhibits scrapie-specific pathology and allows prion replication after inoculation. Scrapie prions administered intraocularly into wild-type mice spread efficiently to the central nervous system within 16 weeks. To determine whether PrP^C is required for scrapie spread, we inoculated prions intraocularly into Prnp^o/o mice containing a PrP-overexpressing neurograft. Neither encephalopathy nor protease-resistant PrP (PrP^Sc) were detected in the grafts for up to 66 weeks. Because grafted PrP-expressing cells elicited an immune response that might have interfered with prion spread, we generated Prnp^o/o mice immunotolerant to PrP and engrafted them with PrP-producing neuroectodermal tissue. Again, intraocular inoculation did not lead to disease in the PrP-producing graft. These results demonstrate that PrP is necessary for prion spread along neural pathways.