Research Papers: Gerotarget (Focus on Aging):

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

Stefania Rigacci, Caterina Miceli, Chiara Nediani _, Andrea Berti, Roberta Cascella, Daniela Pantano, Pamela Nardiello, Ilaria Luccarini, Fiorella Casamenti and Massimo Stefani

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Oncotarget. 2015; 6:35344-35357. https://doi.org/10.18632/oncotarget.6119

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Stefania Rigacci1,*, Caterina Miceli1,*, Chiara Nediani1, Andrea Berti1, Roberta Cascella1, Daniela Pantano2, Pamela Nardiello2, Ilaria Luccarini2, Fiorella Casamenti2 and Massimo Stefani1

1 Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy

2 Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy

* These authors have contributed equally to the work

Correspondence to:

Chiara Nediani, email:

Keywords: oleuropein aglycone, autophagy, neurodegeneration, AMPK, mTOR, Gerotarget

Received: June 30, 2015 Accepted: September 12, 2015 Published: October 14, 2015


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 more in depth the molecular and cellular mechanisms of autophagy induction by OLE using cultured neuroblastoma cells and an OLE-fed mouse model of amylod beta (Aβ) deposition. We found that OLE triggers autophagy in cultured cells through the Ca2+-CAMKKβ–AMPK axis. In particular, in these cells OLE induces a rapid release of Ca2+ from the SR stores which, in turn, activates CAMKKβ, with subsequent phosphorylation and activation of AMPK. The link between AMPK activation and mTOR inhibition was shown in the OLE-fed animal model in which we found that decreased phospho-mTOR immunoreactivity and phosphorylated mTOR substrate p70 S6K levels match enhanced phospho-AMPK levels, supporting the idea that autophagy activation by OLE proceeds through mTOR inhibition. 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.

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