Differences in Scrapie-Induced Pathology of the Retina and Brain in Transgenic Mice that Express Hamster Prion Protein in Neurons, Astrocytes, or Multiple Cell Types

Abstract

Prion protein (PrP) is expressed in many tissues and is required for susceptibility to scrapie and other prion diseases. To investigate the role of PrP expression in different cell types on pathology in retina and brain after scrapie infection, we examined transgenic mice expressing hamster PrP from the PrP promoter (tg7), the neuron-specific enolase promoter (tgNSE), or the astrocyte-specific glial fibrillary acidic protein promoter (tgGFAP). After intraocular inoculation with hamster scrapie, clinical disease developed in tg7 and tgNSE mice by 100 days and in tgGFAP mice by 350 days. Astrogliosis and scrapie-associated protease-resistant PrP (PrP-res) were detected in retina and brain before clinical onset. Retinal PrP-res was present in high amounts in both tg7 and tgNSE mice, however only tg7 mice developed retinal degeneration and extensive apoptosis. In contrast, in all three lines of mice high levels of brain PrP-res accompanied by neurodegeneration were observed. Thus, PrP expression on neurons or astrocytes was sufficient for development of scrapie-induced degeneration in brain but not in retina. The combined effects of PrP-res production in multiple cell types was required to produce retinal degeneration, whereas in brain PrP-res production by neurons or astrocytes alone was sufficient to cause neuronal damage via direct or indirect mechanisms.

Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions

“…Therefore, we established a PMCA reaction using as substrate brain homogenates from tg7 hamster PrP transgenic mice, which express 4-to 5-fold more PrP than hamsters (31). 263K scrapie brain from a terminal stage tg7 mouse containing PrPres was used at a 1:100 dilution to seed the PMCA reaction.…”

Crucial Role for Prion Protein Membrane Anchoring in the Neuroinvasion and Neural Spread of Prion Infection

“…scrapie infection gave 90 to 100% incidence of neuroinvasion and clinical scrapie with incubation periods somewhat longer than the i.c. (35). Therefore, lack of PrP anchoring, rather than low PrPsen levels, appears to account for the low incidence of neuroinvasion seen after i.p.…”

Accelerated Prion Replication in, but Prolonged Survival Times of, Prion-Infected CXCR3−/−Mice

“…4), which may be directly linked to the more pronounced prion accumulation in these animals. Numerous studies have demonstrated that astrocytes are host cells for prion replication in vitro and in vivo (14,16,32,34,48,53,74). Moreover, in vitro astrocyte activation and proliferation were previously shown to result directly from exposure to PrP Sc (21,23,25).…”