Altered distribution, aggregation, and protease resistance of cellular prion protein following intracranial inoculation

Prion protein (PrP C ) is a protease-sensitive and soluble cell surface glycoprotein expressed in almost all mammalian cell types. PrP Sc , a protease-resistant and insoluble form of PrP C , is the causative agent of prion diseases, fatal and transmissible neurogenerative diseases of mammals. Prion infection is initiated via either ingestion or inoculation of PrP Sc or when host PrP C stochastically refolds into PrP Sc . In either instance, the early events that occur during prion infection remain poorly understood. We have used transgenic mice expressing mouse PrP C tagged with a unique antibody epitope to monitor the response of host PrP C to prion inoculation. Following intracranial inoculation of either prion-infected or uninfected brain homogenate, we show that host PrP C can accumulate both intra-axonally and within the myelin membrane of axons suggesting that it may play a role in axonal loss following brain injury. Moreover, in response to the inoculation host PrP C exhibits an increased insolubility and protease resistance similar to that of PrP Sc , even in the absence of infectious prions. Thus, our results raise the possibility that damage to the brain may be one trigger by which PrP C stochastically refolds into pathogenic PrP Sc leading to productive prion infection.