Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis

Friedman-Levi, Yael; Ovadia, Haim; Höftberger, Romana; Einstein, Ofira; Abramsky, Oded; Budka, Herbert; Gabizon, Ruth

doi:10.1128/jvi.00780-07

Cited by 15 publications

(19 citation statements)

References 40 publications

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“…30,31 Shortly, 6-to 8-week-old female C57BL/6 mice were immunized with an emulsion containing 200 μg of MOG (70% purified; synthesized at Hebrew University, Jerusalem, Israel) in saline and an equal volume of complete Freund's adjuvant containing 5 mg/mL H37RA (Difco Laboratories, Detroit, MI, USA). The inoculum (0.2 mL) was injected subcutaneously into right and left flanks.…”

Section: Induction Of Eaementioning

confidence: 99%

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

Binyamin¹,

Larush²,

Frid³

et al. 2015

IJN

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.

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Section: Induction Of Eaementioning

confidence: 99%

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

Binyamin¹,

Larush²,

Frid³

et al. 2015

IJN

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“…In our previous work [20], we showed that mice may succumb to the co-induced scrapie-EAE disease at similar incubation times with very different levels of brain PrP Sc , those varying from undetectable levels to the high levels observed in mice with classical scrapie. To this effect, we next investigated whether mice succumbing to the co-induced disease generate a new prion strain that can transmit disease independent of PrP Sc inoculum levels, or whether disease transmission from these mice correlate with the accumulated PrP Sc levels when in brain homogenates.…”

Section: Resultsmentioning

confidence: 99%

Targeting of prion-infected lymphoid cells to the central nervous system accelerates prion infection

Friedman-Levi

Höftberger

Budka

et al. 2012

J Neuroinflammation

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Background Prions, composed of a misfolded protein designated PrP Sc , are infectious agents causing fatal neurodegenerative diseases. We have shown previously that, following induction of experimental autoimmune encephalomyelitis, prion-infected mice succumb to disease significantly earlier than controls, concomitant with the deposition of PrP Sc aggregates in inflamed white matter areas. In the present work, we asked whether prion disease acceleration by experimental autoimmune encephalomyelitis results from infiltration of viable prion-infected immune cells into the central nervous system. Methods C57Bl/6 J mice underwent intraperitoneal inoculation with scrapie brain homogenates and were later induced with experimental autoimmune encephalomyelitis by inoculation of MOG 35-55 in complete Freund's adjuvant supplemented with pertussis toxin. Spleen and lymph node cells from the co-induced animals were reactivated and subsequently injected into naïve mice as viable cells or as cell homogenates. Control groups were infected with viable and homogenized scrapie immune cells only with complete Freund's adjuvant. Prion disease incubation times as well as levels and sites of PrP Sc deposition were next evaluated. Results We first show that acceleration of prion disease by experimental autoimmune encephalomyelitis requires the presence of high levels of spleen PrP Sc . Next, we present evidence that mice infected with activated prion-experimental autoimmune encephalomyelitis viable cells succumb to prion disease considerably faster than do mice infected with equivalent cell extracts or other controls, concomitant with the deposition of PrP Sc aggregates in white matter areas in brains and spinal cords. Conclusions Our results indicate that inflammatory targeting of viable prion-infected immune cells to the central nervous system accelerates prion disease propagation. We also show that in the absence of such targeting it is the load of PrP Sc in the inoculum that determines the infectivity titers for subsequent transmissions. Both of these conclusions have important clinical implications as related to the risk of prion disease contamination of blood products.

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“…Subsequently, the cells were extensively washed to remove excess nonspecific bound prions, extracted, and normalized for their protein content (see Materials and Methods). Samples were treated with PK and analyzed by Western blot with anti‐PrP mAb IPC1 (Friedman‐Levi et al, 2007) or, omitting the PK digestion step, with anti‐MVM capsid antibody. As depicted in Figure 1a, under these conditions, MVM‐infected cells incorporated significantly more exogenous PrP Sc than control cells.…”

Section: Resultsmentioning

confidence: 99%

“…For example, mastitis in scrapie‐infected sheep, presumably caused by the lentivirus Maedi‐Visna virus (MVV), resulted in deposition of PrP Sc in the inflamed mammary glands (Ligios et al, 2005), and preconditioning of various chronic follicular inflammations in mice induced deposition of PrP Sc and prion infectivity in the sites of infiltration (Heikenwalder et al, 2005). In a recent study, we showed that induction of CNS inflammation in the form of experimental autoimmune encephalomyelitis (EAE) in mice incubating prion disease resulted in early death from an exacerbated EAE‐like syndrome concomitant with deposition of PrP Sc in spinal cord white matter (Friedman‐Levi et al, 2007).…”

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confidence: 99%

Virus‐induced alterations of membrane lipids affect the incorporation of PrP^Sc into cells

Avrahami

Dayan-Amouyal

Tal

et al. 2008

J of Neuroscience Research

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Prion diseases are fatal neurodegenerative disorders characterized by long incubation periods. To investigate whether concurrent diseases can modify the clinical outcome of prion-affected subjects, we tested the effect of viral infection on the binding and internalization of PrP(Sc), essential steps of prion propagation. To this effect, we added scrapie brain homogenate or purified PrP(Sc) to fibroblasts previously infected with minute virus of mice (MVM), a mouse parvovirus. We show here that the rate of incorporation of PrP(Sc) into MVM-infected cells was significantly higher than that observed for naïve cells. Immunostaining of cells and immunoblotting of subcellular fractions using antibodies recognizing PrP and LysoTracker, a lysosomal marker, revealed that in both control and MVM-infected cells the incorporated PrP(Sc) was associated mostly with lysosomes. Interestingly, flotation gradient analysis revealed that the majority of the PrP(Sc) internalized into MVM-infected cells shifted toward raft-containing low-density fractions. Concomitantly, the MVM-infected cells demonstrated increased levels of the glycosphingolipid GM1 (an essential raft lipid component) throughout the gradient and a shift in caveolin 1 (a raft protein marker) toward lighter membrane fractions compared with noninfected cells. Our results suggest that the effect of viral infection on membrane lipid composition may promote the incorporation of exogenous PrP(Sc) into rafts. Importantly, membrane rafts are believed to be the conversion site of PrP(C) to PrP(Sc); therefore, the association of exogenous PrP(Sc) with such membrane microdomains may facilitate prion infection.

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Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis

Cited by 15 publications

References 40 publications

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

Targeting of prion-infected lymphoid cells to the central nervous system accelerates prion infection

Virus‐induced alterations of membrane lipids affect the incorporation of PrP^Sc into cells

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Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis

Cited by 15 publications

References 40 publications

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

Targeting of prion-infected lymphoid cells to the central nervous system accelerates prion infection

Virus‐induced alterations of membrane lipids affect the incorporation of PrPSc into cells

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Virus‐induced alterations of membrane lipids affect the incorporation of PrP^Sc into cells