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. 2013 Jun 19;4(6):973-82.
doi: 10.1021/cn400024q. Epub 2013 Feb 25.

Olive-oil-derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism Against Alzheimer's Disease: In Vitro and in Vivo Studies

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Olive-oil-derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism Against Alzheimer's Disease: In Vitro and in Vivo Studies

Alaa H Abuznait et al. ACS Chem Neurosci. .
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Abstract

Oleocanthal, a phenolic component of extra-virgin olive oil, has been recently linked to reduced risk of Alzheimer's disease (AD), a neurodegenerative disease that is characterized by accumulation of β-amyloid (Aβ) and tau proteins in the brain. However, the mechanism by which oleocanthal exerts its neuroprotective effect is still incompletely understood. Here, we provide in vitro and in vivo evidence for the potential of oleocanthal to enhance Aβ clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major Aβ transport proteins, at the blood-brain barrier (BBB). Results from in vitro and in vivo studies demonstrated similar and consistent pattern of oleocanthal in controlling Aβ levels. In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of (125)I-Aβ40 showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced (125)I-Aβ40 clearance from the brain and increased the BEI% from 62.0 ± 3.0% for control mice to 79.9 ± 1.6% for oleocanthal treated mice. Increased P-gp and LRP1 expression in the brain microvessels and inhibition studies confirmed the role of up-regulation of these proteins in enhancing (125)I-Aβ40 clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in (125)I-Aβ40 degradation as a result of the up-regulation of Aβ degrading enzymes following oleocanthal treatment. In conclusion, these findings provide experimental support that potential reduced risk of AD associated with extra-virgin olive oil could be mediated by enhancement of Aβ clearance from the brain.

Figures

Figure 1
Figure 1
Chemical structure of (−)-oleocanthal.
Figure 2
Figure 2
Representative Western blots for P-gp (A) and LRP1 (B) in bEnd3 cells treated with oleocanthal. Cells were treated for 72 h with increasing concentrations of the indicated compounds in the range of 0.5–50 μM.
Figure 3
Figure 3
Representative fluorescent micrographs of (A) P-gp (green) and (B) LRP1 (red) for control and bEnd3 cells treated with 25 μM of oleocanthal. Quantitative folds change in P-gp and LRP1 expression were measured using ImageJ version 1.44. The data are expressed as mean ± SD (n = 4). *P < 0.05 compared to control untreated cells. Scale bar = 50 μm.
Figure 4
Figure 4
Effect of treatment of bEnd3 cells with vehicle (CTRL) or oleocanthal (OLC) in presence or absence of inhibitors on the intracellular accumulation of radiolabeled 125I-Aβ40. The data are expressed as mean ± SEM (n = 3 independent experiments). *Significantly different from no inhibitor treated cells (P < 0.02). #Significantly different from control treated cells with inhibitors (P < 0.05).
Figure 5
Figure 5
Quantitative analysis for RAGE in bEnd3 cells treated with oleocanthal. Cells were treated for 72 h with 0, 25, and 50 μM concentrations of oleocanthal.
Figure 6
Figure 6
Western blot analysis of P-gp and LRP1 in mice brain microvessels. Significantly higher expression levels of P-gp and LRP1 were detected in oleocanthal (OLC) treated mice compared to control group (CTRL). (A) Representative Western blot lanes for P-gp, LRP1, and protein loading control (β-actin). (B) Quantitative fold increase in P-gp and LRP1 expressions. The data are expressed as mean ± SEM of n = 3 independent experiments (*P < 0.05).
Figure 7
Figure 7
(A) Brain efflux index (BEI) of 125I-Aβ40 in control (CTRL), and oleocanthal (OLC) treated groups measured 24 h after the last injection of oleocanthal or normal saline. Significantly higher BEI% was observed in oleocanthal treated mice compared to control group. (B) Effect of P-gp and LRP1 inhibition by valspodar (24 ng/0.5 μL injection) and RAP (19.5 ng/0.5 μL injection), respectively, on BEI% of 125I-Aβ40 in CTRL and OLC treated groups. Both valspodar and RAP caused a significant reduction in the BEI% in oleocanthal treated group. The data are expressed as mean ± SEM of n = 4–6 (*P < 0.05, ***P < 0.001).
Figure 8
Figure 8
(A) Effect of oleocanthal (OLC) treatment on Aβ degradation in mice brain homogenate compared to control (CTRL) measured using TCA assay. Significantly higher Aβ degradation% was observed in OLC treated mice compared to control. The data are expressed as mean ± SEM of n = 4–6 (*P < 0.05). (B) Representative Western blots lanes for IDE, NEP, and protein loading control (β-actin) in mice brain microvessels. Significantly higher expression levels of IDE but not NEP were detected in OLC treated mice compared to control. (C) Quantitative fold increase in IDE and NEP expressions. The data are expressed as mean ± SEM of n = 3 independent experiments (*P < 0.05).

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