Doxycycline rescues recognition memory and circadian motor rhythmicity but does not prevent terminal disease in fatal familial insomnia mice

Neurobiology of Disease

Luca Imeri¹  Jacopo Lucchetti²  Marco Gobbi²  Ihssane Bouybayoune³  Giada Lavigna³  Ilaria Bertani³  Elena Restelli³  Roberto Chiesa³  Antonio Masone³  Luca Porcu⁴  Stefano Zordan⁵  Mara Rigamonti⁵ 

[1] Department of Health Sciences, University of Milan, Milan, Italy;Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy;Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy;Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy;Tecniplast SpA, Buguggiate, Italy;

关键词: Genetic prion disease;    Prion protein;    PrP;    Protein misfolding;    Transgenic mice;    Pharmacological therapy;   

DOI  :  

来源: DOAJ

【 摘 要 】

Fatal familial insomnia (FFI) is a dominantly inherited prion disease linked to the D178N mutation in the gene encoding the prion protein (PrP). Symptoms, including insomnia, memory loss and motor abnormalities, appear around 50 years of age, leading to death within two years. No treatment is available. A ten-year clinical trial of doxycycline (doxy) is under way in healthy individuals at risk of FFI to test whether presymptomatic doxy prevents or delays the onset of disease.To assess the drug's effect in a tractable disease model, we used Tg(FFI-26) mice, which accumulate aggregated and protease-resistant PrP in their brains and develop a fatal neurological illness highly reminiscent of FFI. Mice were treated daily with 10 mg/kg doxy starting from a presymptomatic stage for twenty weeks. Doxy rescued memory deficits and restored circadian motor rhythmicity in Tg(FFI-26) mice. However, it did not prevent the onset and progression of motor dysfunction, clinical signs and progression to terminal disease. Doxy did not change the amount of aggregated and protease-resistant PrP, but reduced microglial activation in the hippocampus. Presymptomatic doxy treatment rescues cognitive impairment and the motor correlates of sleep dysfunction in Tg(FFI-26) mice but does not prevent fatal disease.

【 授权许可】

Unknown