Review: contribution of transgenic models to understanding human prion disease

Abstract

Transgenic mice expressing human prion protein in the absence of endogenous mouse prion protein faithfully replicate human prions. These models reproduce all of the key features of human disease, including long clinically silent incubation periods prior to fatal neurodegeneration with neuropathological phenotypes that mirror human prion strain diversity. Critical contributions to our understanding of human prion disease pathogenesis and aetiology have only been possible through the use of transgenic mice. These models have provided the basis for the conformational selection model of prion transmission barriers and have causally linked bovine spongiform encephalopathy with variant Creutzfeldt-Jakob disease. In the future these models will be essential for evaluating newly identified potentially zoonotic prion strains, for validating effective methods of prion decontamination and for developing effective therapeutic treatments for human prion disease.

Figure 1

Variant Creutzfeldt-Jakob disease (vCJD) is a distinct human prion strain. (a) Immunoblot of proteinase K digested brain homogenates using antiPrP monoclonal antibody 3F4 showing PrP^Sc types 1–4 in human brain according to the London classification [90]. Types 1–3 PrP^Sc are seen in the brain of classical forms of CJD (either sporadic or iatrogenic CJD) and kuru, while type 4 PrP^Sc is uniquely seen in vCJD brain [25,90,122]. (b,c) Brain sections from sporadic CJD (b) and vCJD (c) showing abnormal PrP accumulation following immunohistochemistry using antiPrP monoclonal antibody ICSM35. Abnormal PrP deposition in sporadic CJD most commonly presents as diffuse, synaptic staining, whereas vCJD is distinguished by the presence of florid PrP plaques consisting of a round amyloid core surrounded by a ring of spongiform vacuoles. Scale bars: 50 µm. (d) Distribution of PrP^Sc in human tissues. The schematic diagram shows tissues in which PrP^Sc has been detected using high sensitivity immunoblotting. The vCJD has a peripheral pathogenesis distinct from classical forms of CJD, with a prominent and uniform involvement of lymphoreticular tissues.

Figure 3

Bovine spongiform encephalopathy (BSE) prions propagate as either variant Creutzfeldt-Jakob disease (vCJD)-like or sporadic CJD (sCJD)-like strains in transgenic mice expressing human prion protein. Primary transmission of BSE prions in transgenic Tg(HuPrP129M^+/+Prnp°^/°)-35 mice (Tg35) results in the propagation of either type 4 PrP^Sc and the occurrence of abundant florid PrP plaques that are the neuropathological hallmark of vCJD or type 2 PrP^Sc and the occurrence of diffuse PrP deposition that is typically seen in sporadic CJD [28]. Molecular and neuropathological characteristics of these distinct prion strains remain stable after secondary passage in the same line of transgenic mice [49]. (a,b) Representative immuno-blots of proteinase-K treated brain homogenates from vCJD and sCJD (PRNP 129 MM genotype with type 2 PrP^Sc; sCJD T2MM) and transgenic mice analysed with antiPrP monoclonal antibody 3F4. The identity of the brain sample is designated above each lane with the type of PrP^Sc present in the sample designated below, using the London classification [90]. (c) Representative immunohistochemical analysis of transgenic mouse brain (thalamus) at secondary passage showing abnormal PrP immunoreactivity, including PrP-positive plaques, stained with antiPrP monoclonal antibody ICSM 35. Scale bars: 100 µm.

Figure 2

Human prion protein with valine at residue 129 prevents expression of the variant Creutzfeldt-Jakob disease (vCJD) phenotype. Primary and secondary transmission of vCJD prions to transgenic Tg(HuPrP129M^+/+Prnp°^/°)-35 mice (Tg35) results in faithful propagation of type 4 PrP^Sc and the occurrence of abundant florid PrP plaques throughout the cortex that are the neuropathological hallmark of vCJD [49]. In contrast, primary transmission of vCJD prions to transgenic Tg(HuPrP129V^+/+Prnp°^/°)-152 mice (Tg152) produces a novel prion strain that is maintained on secondary passage in the same mice distinguished by the propagation of type 5 PrP^Sc and a distinct pattern of neuropathology characterized by large nonflorid PrP plaques restricted to the corpus callosum [26,49]. (a,b) Representative immuno-blots of proteinase-K treated brain homogenates from variant CJD and transgenic mice analysed with antiPrP monoclonal antibody 3F4. The identity of the brain sample is designated above each lane with the type of PrP^Sc present in the sample designated below using the London classification [90]. (c,d) Representative immunohistochemical analysis of transgenic mouse brain at secondary passage showing abnormal PrP plaques stained with antiPrP monoclonal antibodies ICSM 35 (a) or 3F4 (b). Scale bars: 100 µm.