Overwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer's disease (AD). To investigate the relation between mTOR with amyloid-β (Aβ) and tau pathology, we injected an analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent Aβ and tau accumulation associated with a progressive cognitive decline and with a depressive-like phenotype. In particular, 6-month-old 3×Tg-AD and wild-type mice were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline, moreover the mTOR signaling were significantly increased compared to control mice. Everolimus was delivered into the brain by osmotic pump for 4 weeks (2 mg/kg/day). To determine the effects of everolimus on short- and long-term memory, all mice were tested using three behavioural paradigms: the novel object recognition test, the inhibitory avoidance and the Morris water maze. For the depressive-like phenotype, mice were tested by the forced swimming test and the tail suspension test. The expression levels of the main AD hallmarks (APP, Aβ and hyperphosphorylated tau) were evaluated in frontal cortex and hippocampus of 3×Tg-AD mice by western blotting and immunohistochemical experiments. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits and decreased the immobility time in the 3×Tg-AD mice. Western blot analysis have shown that everolimus decreased the expression levels of APP and Aβ oligomers in both brain regions. The phosphorylation levels of tau were not significantly reduced, although a decreasing trend of AT8 positive tau was observed. The Aβ reduction was also confirmed by immunohistochemical analysis. In conclusion, we show that brain infusion with everolimus may represent a valid therapeutic strategy for AD when administered early in the disease progression.

Everolimus rescues the early learning and memory deficits and ameliorates the AD-like pathology in the 3xTg-AD mice / Calcagnini, Silvio; Romano, Adele; Gaetani, Silvana; Dolcetta, Diego; Cassano, Tommaso. - (2017). (Intervento presentato al convegno 17th European Behavioural Pharmacology Society, Biennial meeting, EBPS-2017 tenutosi a Heraklion (Creta, Grecia)).

Everolimus rescues the early learning and memory deficits and ameliorates the AD-like pathology in the 3xTg-AD mice

Calcagnini Silvio
Primo
;
Romano Adele
Secondo
;
Gaetani Silvana;
2017

Abstract

Overwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer's disease (AD). To investigate the relation between mTOR with amyloid-β (Aβ) and tau pathology, we injected an analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent Aβ and tau accumulation associated with a progressive cognitive decline and with a depressive-like phenotype. In particular, 6-month-old 3×Tg-AD and wild-type mice were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline, moreover the mTOR signaling were significantly increased compared to control mice. Everolimus was delivered into the brain by osmotic pump for 4 weeks (2 mg/kg/day). To determine the effects of everolimus on short- and long-term memory, all mice were tested using three behavioural paradigms: the novel object recognition test, the inhibitory avoidance and the Morris water maze. For the depressive-like phenotype, mice were tested by the forced swimming test and the tail suspension test. The expression levels of the main AD hallmarks (APP, Aβ and hyperphosphorylated tau) were evaluated in frontal cortex and hippocampus of 3×Tg-AD mice by western blotting and immunohistochemical experiments. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits and decreased the immobility time in the 3×Tg-AD mice. Western blot analysis have shown that everolimus decreased the expression levels of APP and Aβ oligomers in both brain regions. The phosphorylation levels of tau were not significantly reduced, although a decreasing trend of AT8 positive tau was observed. The Aβ reduction was also confirmed by immunohistochemical analysis. In conclusion, we show that brain infusion with everolimus may represent a valid therapeutic strategy for AD when administered early in the disease progression.
2017
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1342014
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