title: Therapeutic effect of CHF5074, a new γ-secretase modulator, in a mouse model of scrapie.
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.affiliation: Microbiology and Immunology Unit, Department of Veterinary Pathology, Hygiene and Public Health, School of Veterinary Medicine, University of Milan, Milan, Italy. giorgio.poli@unimi.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Poli
authors.forename: Erica
authors.initials: E
authors.lastname: Corda
authors.forename: Barbara
authors.initials: B
authors.lastname: Lucchini
authors.forename: Maria
authors.initials: M
authors.lastname: Puricelli
authors.forename: Piera Anna
authors.initials: PA
authors.lastname: Martino
authors.forename: Paola
authors.initials: P
authors.lastname: Dall'ara
authors.forename: Gino
authors.initials: G
authors.lastname: Villetti
authors.forename: Silvio R
authors.initials: SR
authors.lastname: Bareggi
authors.forename: Cristiano
authors.initials: C
authors.lastname: Corona
authors.forename: Elena
authors.initials: E
authors.lastname: Vallino Costassa
authors.forename: Paola
authors.initials: P
authors.lastname: Gazzuola
authors.forename: Barbara
authors.initials: B
authors.lastname: Iulini
authors.forename: Maria
authors.initials: M
authors.lastname: Mazza
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Acutis
authors.forename: Paolo
authors.initials: P
authors.lastname: Mantegazza
authors.forename: Cristina
authors.initials: C
authors.lastname: Casalone
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Imbimbo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D051379:Mice; D018620:PrPSc Proteins / Q000378:metabolism; D012608:Scrapie / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis
chemical_list: C522246:1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid; D003521:Cyclopropanes; D018620:PrPSc Proteins; D005480:Flurbiprofen; D053829:Amyloid Precursor Protein Secretases