Entry #: 4
Date: 4 July 2017
Section: Phenolic compounds
Topic: Oleocanthal and Alzheimer’s disease
Type: Molecular mechanism
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D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis
Olive-oil-derived oleocanthal enhances β-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: In vitro and in vivo studies
Abuznait et. al.
Citation / Year
(1) / 2013
Alzheimer’s disease, oleocanthal, β-amyloid, P-glycoprotein, lipoprotein receptor related protein-1, insulin degrading enzyme (insulysin)
Accumulating evidence indicates the beneficial effects of the Mediterranean diet in cognitive decline and Alzheimer’s disease. The effects are attributed in part to the consumption of extra-virgin olive oil and particularly due to the phenolic compounds in the oil, which includes oleocanthal. A number of previous studies have investigated the beneficial effects of oleocanthal in models neurodegenerative conditions and Alzheimer’s disease. Oleocanthal has been shown to act on tau fibrillization (2, 3), and aggregation and β-amyloid (Aβ) oligomerization and aggregation (4), the two major hallmarks of Alzheimer’s disease. The overall aim of this study was to investigate further mechanisms of action of oleocanthal in cell culture and in vivo models of Alzheimer’s pathology. Specifically, the effect of the accumulation and clearance of the Aβ40 peptide was investigated in endothelial cells and in vivo by examining cellular uptake and efflux of the pathogenic peptide from the brain.
Key points and implications
The findings indicated that treatment of bEnd3 cells with oleocanthal resulted in the increased expression of the major transport proteins, P-glycoprotein (Pgp) (5), and lipoprotein receptor related protein-1 (LRP1) (6), which are well-known to be involved in Alzheimer’s pathology. It noteworthy that 1) bEnd3 cells are a mouse endothelialpolyoma middle T antigen transformed line and 2) the findings from immunofluorescence studies were much more convincing than the immunoblots. It was shown that oleocanthal did not have an effect on the expression of the receptor for advanced glycation end products (RAGE) which is known to regulate Aβ influx through the blood-brain-barrier (BBB) into the brain (7). A series of neat studies using radiolabelled (125I) Aβ40 peptide and inhibitors for Pgp (verapamil in cell cultures and valspodar in vivo) and receptor associated protein (RAP) for LRP1 indicated regulation of cellular uptake and enhanced brain clearance of 125IAβ40 by oleocanthal, is mediated, at least in part, by modulation of the key transport proteins. Further, it was shown that oleocanthal degradation of Aβ in mouse brain homogenates which was associated with an increased in expression of the insulin degrading enzyme (IDE) peptidase which is known to cleave and degrade Aβ. The findings indicated that oleocanthal did not significantly alter the expression of neprilysin (NEP) in mouse brain homogenates however, as stated by the authors oleocanthal was shown to modulate NEP in vitro; NEP another key peptidase known to cleave and degrade Aβ.
In summary this study indicates that oleocanthal has the potential to alter the metabolism and transportation of Aβ at the BBB by modulating: 1) the key transport proteins Pgp and LRP1 and 2) peptidases (IDE indicated in this study). Overall this study provides additional potential mechanisms of action accounting for the beneficial effects of oleocanthal, and more generally, of the Mediterranean diet with consumption of extra-virgin olive oil, in models of Alzheimer’s disease.
- A. H. Abuznait, H. Qosa, B. A. Busnena, K. A. El Sayed, A. Kaddoumi, Olive-oil-derived oleocanthal enhances beta-amyloid clearance as a potential neuroprotective mechanism against Alzheimer’s disease: in vitro and in vivo studies. ACS Chem Neurosci 4, 973-982 (2013).
- W. Li et al., Inhibition of tau fibrillization by oleocanthal via reaction with the amino groups of tau. J Neurochem 110, 1339-1351 (2009).
- M. C. Monti, L. Margarucci, A. Tosco, R. Riccio, A. Casapullo, New insights on the interaction mechanism between tau protein and oleocanthal, an extra-virgin olive-oil bioactive component. Food Funct 2, 423-428 (2011).
- J. Pitt et al., Alzheimer’s-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicol Appl Pharmacol 240, 189-197 (2009).
- D. Kuhnke et al., MDR1-P-Glycoprotein (ABCB1) Mediates Transport of Alzheimer’s amyloid-beta peptides–implications for the mechanisms of Abeta clearance at the blood-brain barrier. Brain Pathol 17, 347-353 (2007).
- M. Shibata et al., Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest 106, 1489-1499 (2000).
- S. D. Yan et al., RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382, 685-691 (1996).
- I. V. Kurochkin, S. Goto, Alzheimer’s beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme. FEBS Lett 345, 33-37 (1994).
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