Authors: Giorgio Poli, Erica Corda, Barbara Lucchini, Maria Puricelli, Piera Anna Martino, Paola Dall’Ara, Gino Villetti, Silvio R. Bareggi, Cristiano Corona, Elena Vallino Costassa, Paola Gazzuola, Barbara Iulini, Maria Mazza, Pierluigi Acutis, Paolo Mantegazza, Cristina Casalone and Bruno P. Imbimbo
Corresponding author: giorgio.poli@unimi.it
Department of Veterinary Pathology, Hygiene and Public Health; Microbiology and Immunology Unit; School of Veterinary Medicine; University of Milan; Milan, Italy
Erica Corda
Department of Veterinary Pathology, Hygiene and Public Health; Microbiology and Immunology Unit; School of Veterinary Medicine; University of Milan; Milan, Italy
Barbara Lucchini
Department of Veterinary Pathology, Hygiene and Public Health; Microbiology and Immunology Unit; School of Veterinary Medicine; University of Milan; Milan, Italy
Maria Puricelli
Department of Veterinary Pathology, Hygiene and Public Health; Microbiology and Immunology Unit; School of Veterinary Medicine; University of Milan; Milan, Italy
Piera Anna Martino
Department of Veterinary Pathology, Hygiene and Public Health; Microbiology and Immunology Unit; School of Veterinary Medicine; University of Milan; Milan, Italy
Paola Dall’Ara
Department of Veterinary Pathology, Hygiene and Public Health; Microbiology and Immunology Unit; School of Veterinary Medicine; University of Milan; Milan, Italy
Gino Villetti
Research and Development; Chiesi Farmaceutici; Parma, Italy
Silvio R. Bareggi
Department of Pharmacology, Chemotherapy and Medical Toxicology; School of Medicine; University of Milan; Milan, Italy
Cristiano Corona
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Elena Vallino Costassa
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Paola Gazzuola
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Barbara Iulini
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Maria Mazza
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Pierluigi Acutis
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Paolo Mantegazza
Department of Pharmacology, Chemotherapy and Medical Toxicology; School of Medicine; University of Milan; Milan, Italy
Cristina Casalone
CEA; Italian Reference Laboratory for TSEs; Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Turin, Italy
Bruno P. Imbimbo
Research and Development; Chiesi Farmaceutici; Parma, Italy
In transmissible spongiform encephalopathies (TSEs) and Alzheimer disease (AD) both misfolding and aggregation of specific proteins represent key features. Recently, it was observed that PrPc 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 d longer than vehicle-treated mice (p < 0.001). In these animals, immunohistochemistry analyses showed that deposition of PrPSc 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 with 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 PrPSc 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.
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