期刊
NEUROBIOLOGY OF DISEASE
卷 158, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105455
关键词
Genetic prion disease; Prion protein; PrP; Protein misfolding; Transgenic mice; Pharmacological therapy
资金
- Fondazione Telethon Italy [GGP10208]
- EC [ERARE14-fp-097-CHAPRION]
- Italian Ministry of Health [RF-2016-02362950]
Doxycycline shows some therapeutic effects in the FFI mouse model, improving cognitive impairment and motor symptoms associated with sleep dysfunction, but it does not prevent the onset and progression of the disease, nor does it change the amount of aggregated protein or microglial activation.
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.
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