Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: A mechanistic insight

The healthy effects of plant polyphenols, some of which characterize the so-called Mediterranean diet, have been shown to arise from epigenetic and biological modifications resulting, among others, in autophagy stimulation. Our previous work highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the extra virgin olive oil, against neurodegeneration both in cultured cells and in model organisms, focusing, in particular, autophagy activation. In this study we investigated the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and a mouse model of Aβ deposition. We found that OLE triggers autophagy both in cultured cells and in the animal model through the Ca2+-CaMKKβ-AMPK-mTOR axis. In particular, in cultured cells OLE induces a rapid release of Ca2+ from the ER stores which, in turn, activates CaMKKβ, with subsequent phosphorylation and activation of AMPK, inhibition of mTOR and autophagy ignition. Our results agree with those reported for other plant polyphenols, suggesting a shared molecular mechanism underlying the healthy effects of these substances against ageing, neurodegeneration, cancer, diabetes and other diseases implying autophagy dysfunction.