PROTEINASE-RESISTANT PRION PROTEIN ACCUMULATION IN SYRIAN-HAMSTER BRAIN CORRELATES WITH REGIONAL PATHOLOGY AND SCRAPIE INFECTIVITY

Multiple lines of evidence indicate that PrP(Sc), found only in scrapie, is a necessary component of the infectious scrapie agent. Equally compelling is the evidence that its accumulation in the brain causes the neuropathology characteristic of scrapie. We measured the regional concentration of PrP(Sc) in nine brain regions throughout the course of scrapie in the Syrian hamster following intrathalamic inoculation of prions. PrP(Sc) was compared to the regional concentration of glial fibrillary acidic protein, a measure of reactive astrocytic gliosis. PrP(Sc) was detected first in the thalamus 14 to 21 days postinoculation and next in the septum at 28 days. Initiation of PrP(Sc) synthesis and accumulation in the thalamus was attributable to the inoculum and in the septum to ventricular spread of de novo synthesized PrP(Sc). The timing and pattern of PrP(Sc) accumulation in all other brain regions suggested transmission along neuroanatomic pathways. Reactive astrocytic gliosis followed PrP(Sc) accumulation in each region by 1 to 2 weeks. Brain PrP(Sc), determined by summing the concentrations in each brain region, correlated well with scrapie infectivity titers throughout the course of infection (correlation coefficient = 0.975; slope of linear regression line + 1.136). Our results support the hypothesis that PrP(Sc) participates in both the etiology and pathogenesis of prion diseases.