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.