The pathogenesis of
scrapie in sheep after natural or oral exposure to the infectious agent generally involves the early accumulation of disease-associated
prion protein (
PrP(d)) in the lymphoreticular system (LRS). This phase is followed by neuroinvasion, for which two routes, ascending neural and haematogenous, have been postulated. The present study reports the use of immunohistochemistry to track the tissue progression of
PrP(d) deposition in sheep of a single, highly
scrapie-susceptible PrP genotype administered by the oral or conjunctival routes. Regardless of the route of
infection, the earliest detection of
PrP(d) was in gut- and pharynx-associated LRS tissues. Subsequently, the brain became
PrP(d) positive simultaneously with other LRS tissues, but before the spinal cord and peripheral nervous tissues of the enteric, parasympathetic and sympathetic systems. The sites of initial
PrP(d) accumulation in the brain were the dorsal motor nucleus of the vagus and the hypothalamus and their related circumventricular organs (the area postrema and the median eminence, respectively). These were the same for both routes of
infection. Rapid progression to clinical disease was observed in sheep infected orally or conjunctivally, with definite signs of
scrapie recorded at around 6 and 8 months after
infection, respectively. Longer incubation periods in sheep infected by the conjunctival route were probably due to them receiving a lower dose than those infected orally. Irrespective of the route of
infection, clinically affected sheep showed the same pathological phenotype (
PrP(d) profile) and
PrP(d) distribution throughout the brain. The identical peripheral and central pathogenesis observed in sheep of both groups suggests early dissemination of the infectious agent in the bloodstream and a common neuroinvasion pathway. The late involvement of the enteric and autonomic nervous system supports a haematogenous route of
infection to the brain.