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Therapeutic effect of CHF5074, a new γ-secretase modulator, in a mouse model of scrapie.
Prion. 2012 Jan-Mar; 6(1):62-72.P

Abstract

In Transmissible Spongiform Encephalopathies (TSEs) and Alzheimer disease (AD) both misfolding and aggregation of specific proteins represent key features. Recently, it was observed that PrP (c) is a mediator of a synaptic dysfunction induced by Aβ oligomers. We tested a novel γ secretase modulator (CHF5074) in a murine model of prion disease. Groups of female mice were intracerebrally or intraperitoneally infected with the mouse-adapted Rocky Mountain Laboratory prions. Two weeks prior infection, the animals were provided with a CHF5074-medicated diet (375 ppm) or a standard diet (vehicle) until they showed neurological signs and eventually died. In intracerebrally infected mice, oral administration of CHF5074 did not prolong survival of the animals. In intraperitoneally-infected mice, CHF5074-treated animals showed a median survival time of 21 days longer than vehicle-treated mice (p < 0.001). In these animals, immunohistochemistry analyses showed that deposition of PrP (Sc) in the cerebellum, hippocampus and parietal cortex in CHF5074-treated mice was significantly lower than in vehicle-treated animals. Immunostaining of glial fibrillary acidic protein (GFAP) in parietal cortex revealed a significantly higher reactive gliosis in CHF5074-treated mice compared to the control group of infected animals. Although the mechanism underlying the beneficial effects of CHF5074 in this murine model of human prion disease is unclear, it could be hypothesized that the drug counteracts PrP (Sc) toxicity through astrocyte-mediated neuroprotection. CHF5074 shows a pharmacological potential in murine models of both AD and TSEs thus suggesting a link between these degenerative pathologies.

Authors+Show Affiliations

Microbiology and Immunology Unit, Department of Veterinary Pathology, Hygiene and Public Health, School of Veterinary Medicine, University of Milan, Milan, Italy. giorgio.poli@unimi.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22453180

Citation

Poli, Giorgio, et al. "Therapeutic Effect of CHF5074, a New Γ-secretase Modulator, in a Mouse Model of Scrapie." Prion, vol. 6, no. 1, 2012, pp. 62-72.
Poli G, Corda E, Lucchini B, et al. Therapeutic effect of CHF5074, a new γ-secretase modulator, in a mouse model of scrapie. Prion. 2012;6(1):62-72.
Poli, G., Corda, E., Lucchini, B., Puricelli, M., Martino, P. A., Dall'ara, P., Villetti, G., Bareggi, S. R., Corona, C., Vallino Costassa, E., Gazzuola, P., Iulini, B., Mazza, M., Acutis, P., Mantegazza, P., Casalone, C., & Imbimbo, B. P. (2012). Therapeutic effect of CHF5074, a new γ-secretase modulator, in a mouse model of scrapie. Prion, 6(1), 62-72. https://doi.org/10.4161/pri.6.1.18317
Poli G, et al. Therapeutic Effect of CHF5074, a New Γ-secretase Modulator, in a Mouse Model of Scrapie. Prion. 2012 Jan-Mar;6(1):62-72. PubMed PMID: 22453180.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic effect of CHF5074, a new γ-secretase modulator, in a mouse model of scrapie. AU - Poli,Giorgio, AU - Corda,Erica, AU - Lucchini,Barbara, AU - Puricelli,Maria, AU - Martino,Piera Anna, AU - Dall'ara,Paola, AU - Villetti,Gino, AU - Bareggi,Silvio R, AU - Corona,Cristiano, AU - Vallino Costassa,Elena, AU - Gazzuola,Paola, AU - Iulini,Barbara, AU - Mazza,Maria, AU - Acutis,Pierluigi, AU - Mantegazza,Paolo, AU - Casalone,Cristina, AU - Imbimbo,Bruno P, PY - 2012/3/29/entrez PY - 2012/3/29/pubmed PY - 2012/8/11/medline SP - 62 EP - 72 JF - Prion JO - Prion VL - 6 IS - 1 N2 - In Transmissible Spongiform Encephalopathies (TSEs) and Alzheimer disease (AD) both misfolding and aggregation of specific proteins represent key features. Recently, it was observed that PrP (c) is a mediator of a synaptic dysfunction induced by Aβ oligomers. We tested a novel γ secretase modulator (CHF5074) in a murine model of prion disease. Groups of female mice were intracerebrally or intraperitoneally infected with the mouse-adapted Rocky Mountain Laboratory prions. Two weeks prior infection, the animals were provided with a CHF5074-medicated diet (375 ppm) or a standard diet (vehicle) until they showed neurological signs and eventually died. In intracerebrally infected mice, oral administration of CHF5074 did not prolong survival of the animals. In intraperitoneally-infected mice, CHF5074-treated animals showed a median survival time of 21 days longer than vehicle-treated mice (p < 0.001). In these animals, immunohistochemistry analyses showed that deposition of PrP (Sc) in the cerebellum, hippocampus and parietal cortex in CHF5074-treated mice was significantly lower than in vehicle-treated animals. Immunostaining of glial fibrillary acidic protein (GFAP) in parietal cortex revealed a significantly higher reactive gliosis in CHF5074-treated mice compared to the control group of infected animals. Although the mechanism underlying the beneficial effects of CHF5074 in this murine model of human prion disease is unclear, it could be hypothesized that the drug counteracts PrP (Sc) toxicity through astrocyte-mediated neuroprotection. CHF5074 shows a pharmacological potential in murine models of both AD and TSEs thus suggesting a link between these degenerative pathologies. SN - 1933-690X UR - https://www.unboundmedicine.com/medline/citation/22453180/Therapeutic_effect_of_CHF5074_a_new_γ_secretase_modulator_in_a_mouse_model_of_scrapie_ L2 - https://www.tandfonline.com/doi/full/10.4161/pri.6.1.18317 DB - PRIME DP - Unbound Medicine ER -