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

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 Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) 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. The mTOR enzymatic activity and the levels of phosphorylated p70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis. We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice. In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression.