Numerous clinical and preclinical studies have suggested several health promoting effects for the dietary consumption of extra-virgin olive oil (EVOO) that could protect and decrease the risk of developing Alzheimer’s disease (AD). Moreover, recent studies have linked this protective effect to oleocanthal, a phenolic secoiridoid component of EVOO. This protective effect of oleocanthal against AD has been related to its ability to prevent amyloid-β (Aβ) and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type mice in vivo; however, its effect in a mouse model of AD is not known. In the current study, we investigated the effect of oleocanthal on pathological hallmarks of AD in TgSwDI, an animal model of AD. Mice treatment for 4 weeks with oleocanthal significantly decreased amyloid load in the hippocampal parenchyma and microvessels. This reduction was associated with enhanced cerebral clearance of Aβ across the blood-brain barrier (BBB). Further mechanistic studies demonstrated oleocanthal to increase the expression of important amyloid clearance proteins at the BBB including P-glycoprotein and LRP1, and to activate the ApoE-dependent amyloid clearance pathway in the mice brains. The anti-inflammatory effect of oleocanthal in the brains of these mice was also obvious where it was able to reduce astrocytes activation and IL-1β levels. Finally, we could recapitulate the observed protective effect of oleocanthal in an in vitro human-based model, which could argue against species difference in response to oleocanthal. In conclusion, findings from in vivo and in vitro studies provide further support for the protective effect of oleocanthal against the progression of AD.
Mediterranean diet is considered one of the most important healthy habits of the Mediterranean population. Emerging evidence from clinical studies has correlated Mediterranean diets to the low risk of several noncommunicable diseases such as cardiovascular disease and certain types of cancers.1−3 Moreover, a very recent study reported that nutrition intervention with Mediterranean diet to significantly improve the participants’ cognitive performance.4 Mediterranean diet contains several elements that were evaluated for their health promoting effect.5,6 Extra-virgin olive oil (EVOO) is one of the characteristic elements of Mediterranean diet that has been extensively studied for its potential health promoting activities.5,7 Several clinical studies have shown the enrichment of Mediterranean diet with EVOO to improve cognitive performance and slow the progression of memory impairment.3,4,8,9 EVOO is defined as a high quality olive oil that is obtained from the first pressing of olive fruit by mechanical means (European Commission, 2003). EVOO has long been recognized for its extraordinary fat content, which is composed of two fractions, the glycerol (∼95%) and nonglycerol (∼5%) fractions.10 About 75% of fat content of EVOO (in its glycerol fraction) is in the form of oleic acid (a monounsaturated, omega-9 fatty acid) that was previously reported to improve cardiovascular functions such as reduction in blood cholesterol and blood pressure.11 The nonglycerol fraction contains phenolic compounds that account for EVOO resistance to oxidative rancidity.12 Most of EVOO phenolic compounds are antioxidant molecules that are able to counter the toxic effects of oxygen metabolism such as free radical formation, thus protecting cells against oxidative damage.13,14 The total nonglycerol content of EVOO is about 500 mg/kg and includes over 30 chemical substances belonging to different classes, such as alcohols, sterols, hydrocarbons, and volatile compounds.5 The most abundant phenolic compounds in EVOO are tyrosol, hydroxytyrosol, and other complex ester secoiridoids, which share the hydroxytyrosol or tyrosol alcohol moiety. Among EVOO phenolics, S(−)-oleocanthal, a dialdehydic form of (−)-deacetoxyligstroside glycoside, is a naturally occurring phenolic secoiridoid that has related chemical structure to the secoiridoids ligstroside and oleuropein aglycones, which are common in EVOO. Oleocanthal is responsible for the bitter and pungent taste of EVOO, and has anti-inflammatory and antioxidant properties similar to the nonsteroidal anti-inflammatory drug ibuprofen.15
Several animal and in vitro studies have shown that oleocanthal and phenolic compounds of EVOO possess important neuroprotective activities against Alzheimer’s disease (AD).16−20 In vitro studies with oleocanthal demonstrated its effect on the key mediators of AD pathogenesis, amyloid-β (Aβ) and hyperphosphorylated tau proteins,16,21,22 which contribute significantly to neurodegeneration and memory loss.23 In these studies, oleocanthal prevented the aggregation of hyperphosphorylated tau by locking tau into the naturally unfolded state,21 and altered the oligomerization state of soluble Aβ42 oligomers that protected neurons from their synaptopathological effect.22 In addition, we recently showed the ability of oleocanthal to enhance cerebrovascular clearance of exogenous Aβ across the blood-brain barrier (BBB) of wild type mice brains.16
While previous in vitro studies and our in vivo study in wild type mice provided insights on the mechanisms of oleocanthal neuroprotective activity, none of these studies tested the reported beneficial effects of oleocanthal in an AD model. Therefore, in the current study, we examined the effect of oleocanthal on Aβ load in the brain parenchyma of a mouse model of AD, namely, TgSwDI mice, and on Aβ deposit on brain microvessels. In addition, the effect of oleocanthal on cerebral clearance and production of Aβ, tau hyperphosphorylation and its anti-inflammatory effect on astrocytes and brain inflammatory cytokines release were investigated. To test whether the observed effects in the mouse model could be extended to humans, we studied the effect of oleocanthal on Aβ clearance and production using a cell-based in vitro model.