title: Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight.
abstract: 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.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rigacci
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Miceli
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Nediani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Berti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cascella
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pantano
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Nardiello
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Luccarini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Casamenti
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Stefani
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology*; D051379:Mice; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D057888:Iridoid Glucosides; D039823:Iridoids; C002769:oleuropein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Gerotarget; autophagy; mTOR; neurodegeneration; oleuropein aglycone