Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer's Disease: In Vitro and in Vivo Studies

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 beta-amyloid (A beta) 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 A beta clearance from the brain via up-regulation of P-glycoprotein (P-gp) and LDL lipoprotein receptor related protein-1 (LRP1), major A beta 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 A beta levels. In cultured mice brain endothelial cells, oleocanthal treatment increased P-gp and LRP1 expression and activity. Brain efflux index (BEI%) studies of I-125-A beta(40) showed that administration of oleocanthal extracted from extra-virgin olive oil to C57BL/6 wild-type mice enhanced I-125-A beta(40) 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 I-125-A beta(40) clearance after oleocanthal treatment. Furthermore, our results demonstrated significant increase in I-125-A beta(40) degradation as a result of the up-regulation of A beta 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 A beta clearance from the brain.