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.
Highlights
An increasing body of evidence points to a number of natural polyphenols as protective tools against cell sufferance and death in a wide number of human pathologies spanning from neurodegenerative to cardiovascular diseases, cancer and diabetes, including ageing
We previously showed that diet supplementation with oleuropein aglycone (OLE) strongly ameliorates Alzheimer’s disease (AD)-associated symptoms in TgCRND8 mice, a model of Aβ deposition, in several ways, including induction of autophagy [21,22,23]; a similar www.impactjournals.com/oncotarget behaviour was shown in OLE-treated murine N2a neuroblastoma cells [23]
We initially exposed the cells to 50 μM OLE for 24 h, the conditions we previously reported to trigger autophagy in N2a cells [23] and checked the cells for both Beclin-1 level and adenosine monophosphatedependent protein kinase (AMPK) phosphorylation
Summary
An increasing body of evidence points to a number of natural polyphenols as protective tools against cell sufferance and death in a wide number of human pathologies spanning from neurodegenerative to cardiovascular diseases, cancer and diabetes, including ageing. These molecules include compounds such as resveratrol, epigallocatechin-3-gallate (EGCG), curcumin, morin, quercetin and oleuropein aglycone (OLE) found in a number of foods of plant origin and believed to be at the basis of the claimed beneficial properties of these foods [1]. One of these is their ability to raise, in a number of different cell types, the autophagic response involved in protection against neurodegeneration, liver and vascular diseases [4,5,6]
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