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Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.

ABSTRACT: We investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatydylinositol membrane anchor. In the brain, blood, and heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per milliliter. The hearts of these transgenic mice contained PrPres-positive amyloid deposits that led to myocardial stiffness and cardiac disease.

SUBMITTER: Trifilo MJ

PROVIDER: S-EPMC1820586 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.

Trifilo Matthew J MJ Yajima Toshitaka T Gu Yusu Y Dalton Nancy N Peterson Kirk L KL Race Richard E RE Meade-White Kimberly K Portis John L JL Masliah Eliezer E Knowlton Kirk U KU Chesebro Bruce B Oldstone Michael B A MB

Science (New York, N.Y.) 20060701 5783

We investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatydylinositol membrane anchor. In the brain, blood, and heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per milliliter. The hearts of these transgenic mice contained ...[more]

PMID: 16825571

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Project description:Transgenic (Tg) mice expressing chimeras of mouse and human prion proteins (PrPs) have shorter incubation periods for Creutzfeldt-Jakob disease (CJD) prions than mice expressing full-length human PrP. Increasing the sequence similarity of the chimeric PrP to mouse PrP, by reverting human residues to mouse, resulted in a Tg line, denoted Tg22372, which was susceptible to sporadic (s) CJD prions in approximately 110 days.Mice expressing chimeric mouse/human PrP transgenes were produced. The mice were inoculated intracerebrally with extracts prepared from the brains of patients who died of CJD. Onset of neurological dysfunction marked the end of the incubation time. After sacrifice of the Tg mice, their brains were analyzed for PrP(Sc) and neuropathological changes.Reversion of 1 additional residue (M111V) resulted in a new Tg line, termed Tg1014, susceptible to sCJD prions in approximately 75 days. Tg1014 mice also have shorter incubation periods for variant (v) CJD prions, providing a more tractable model for studying this prion strain. Transmission of vCJD prions to Tg1014 mice resulted in 2 different strains, determined by neuropathology and biochemical analysis, which correlated with the length of the incubation time. One strain had the biochemical, neuropathological, and transmission characteristics, including longer incubation times, of the inoculated vCJD strain; the second strain produced a phenotype resembling that of sCJD prions including relatively shorter incubation periods. Mice with intermediate incubation periods for vCJD prions had a mixture of the 2 strains. Both strains were serially transmitted in Tg1014 mice, which led to further reduction in incubation periods. Conversion of vCJD-like to sCJD-like strains was favored in Tg1014 mice more than in the Tg22372 line. The single amino acid difference therefore appears to offer selective pressure for propagation of the sCJD-like strain.These 2 Tg mouse lines provide relatively rapid models to study human prion diseases as well as the evolution of human prion strains.

Dataset Information

Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.

Publications

Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.

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