TY - JOUR
T1 - Early intrathecal infusion of everolimus restores cognitive function and mood in a murine model of Alzheimer's disease
AU - Cassano, Tommaso
AU - Magini, Alessandro
AU - Giovagnoli, Stefano
AU - Polchi, Alice
AU - Calcagnini, Silvio
AU - Pace, Lorenzo
AU - Lavecchia, Michele Angelo
AU - Scuderi, Caterina
AU - Bronzuoli, Maria Rosanna
AU - Ruggeri, Loredana
AU - Gentileschi, Maria Pia
AU - Romano, Adele
AU - Gaetani, Silvana
AU - De Marco, Federico
AU - Emiliani, Carla
AU - Dolcetta, Diego
PY - 2018/1
Y1 - 2018/1
N2 - The discovery that mammalian target of rapamycin (mTOR) inhibition increases lifespan in mice and restores/delays many aging phenotypes has led to the identification of a novel potential therapeutic target for the treatment of Alzheimer's disease (AD). Among mTOR inhibitors, everolimus, which has been developed to improve the pharmacokinetic characteristics of rapamycin, has been extensively profiled in preclinical and clinical studies as anticancer and immunosuppressive agent, but no information is available about its potential effects on neurodegenerative disorders. Using a reliable mouse model of AD (3 × Tg-AD mice), we explored whether short-term treatment with everolimus injected directly into the brain by osmotic pumps was able to modify AD-like pathology with low impact on peripheral organs. We first established in non-transgenic mice the stability of everolimus at 37 °C in comparison with rapamycin and, then, evaluated its pharmacokinetics and pharmacodynamics profiles through either a single peripheral (i.p.) or central (i.c.v.) route of administration. Finally, 6-month-old (symptomatic phase) 3 × Tg-AD mice were treated with continuous infusion of either vehicle or everolimus (0.167 μg/μl/day, i.c.v.) using the osmotic pumps. Four weeks after the beginning of infusion, we tested our hypothesis following an integrated approach, including behavioral (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses. Everolimus (i) showed higher stability than rapamycin at 37 °C, (ii) poorly crossed the blood-brain barrier after i.p. injection, (iii) was slowly metabolized in the brain due to a longer t 1/2 in the brain compared to blood, and (iv) was more effective in the CNS when administered centrally compared to a peripheral route. Moreover, the everolimus-induced mTOR inhibition reduced human APP/Aβ and human tau levels and improved cognitive function and depressive-like phenotype in the 3 × Tg-AD mice. The intrathecal infusion of everolimus may be effective to treat early stages of AD-pathology through a short and cyclic administration regimen, with short-term outcomes and a low impact on peripheral organs.
AB - The discovery that mammalian target of rapamycin (mTOR) inhibition increases lifespan in mice and restores/delays many aging phenotypes has led to the identification of a novel potential therapeutic target for the treatment of Alzheimer's disease (AD). Among mTOR inhibitors, everolimus, which has been developed to improve the pharmacokinetic characteristics of rapamycin, has been extensively profiled in preclinical and clinical studies as anticancer and immunosuppressive agent, but no information is available about its potential effects on neurodegenerative disorders. Using a reliable mouse model of AD (3 × Tg-AD mice), we explored whether short-term treatment with everolimus injected directly into the brain by osmotic pumps was able to modify AD-like pathology with low impact on peripheral organs. We first established in non-transgenic mice the stability of everolimus at 37 °C in comparison with rapamycin and, then, evaluated its pharmacokinetics and pharmacodynamics profiles through either a single peripheral (i.p.) or central (i.c.v.) route of administration. Finally, 6-month-old (symptomatic phase) 3 × Tg-AD mice were treated with continuous infusion of either vehicle or everolimus (0.167 μg/μl/day, i.c.v.) using the osmotic pumps. Four weeks after the beginning of infusion, we tested our hypothesis following an integrated approach, including behavioral (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses. Everolimus (i) showed higher stability than rapamycin at 37 °C, (ii) poorly crossed the blood-brain barrier after i.p. injection, (iii) was slowly metabolized in the brain due to a longer t 1/2 in the brain compared to blood, and (iv) was more effective in the CNS when administered centrally compared to a peripheral route. Moreover, the everolimus-induced mTOR inhibition reduced human APP/Aβ and human tau levels and improved cognitive function and depressive-like phenotype in the 3 × Tg-AD mice. The intrathecal infusion of everolimus may be effective to treat early stages of AD-pathology through a short and cyclic administration regimen, with short-term outcomes and a low impact on peripheral organs.
KW - 3 × Tg-AD mice
KW - Alzheimer's disease
KW - Depression
KW - Everolimus
KW - Intrathecal administration
KW - Learning and memory
KW - Mammalian target of rapamycin
UR - http://www.scopus.com/inward/record.url?scp=85054038808&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054038808&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2018.09.011
DO - 10.1016/j.expneurol.2018.09.011
M3 - Article
C2 - 30243986
AN - SCOPUS:85054038808
VL - 311
SP - 88
EP - 105
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
ER -