Oleocanthal-Rich Extra-Virgin Olive Oil Restores the Blood–Brain Barrier Function through NLRP3 Inflammasome Inhibition Simultaneously with Autophagy Induction in TgSwDI Mice

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by multiple hallmarks including extracellular amyloid (Aβ) plaques, neurofibrillary tangles, dysfunctional blood-brain barrier (BBB), neuroinflammation, and impaired autophagy. Thus, novel strategies that target multiple disease pathways would be essential to prevent, halt, or treat the disease. A growing body of evidence including our studies supports a protective effect of oleocanthal (OC) and extra-virgin olive oil (EVOO) at early AD stages before the onset of pathology. In addition, we reported previously that OC and EVOO exhibited such effect by restoring the BBB function; however, the mechanism(s) by which OC and EVOO exert such an effect and whether this effect extends to a later stage of AD remain unknown. In this work, we sought first to test the effect of OC-rich EVOO consumption at an advanced stage of the disease in TgSwDI mice, an AD mouse model, starting at the age of 6 months for 3 months treatment, and then to elucidate the mechanism(s) by which OC-rich EVOO exerts the observed beneficial effect. Overall findings demonstrated that OC-rich EVOO restored the BBB function and reduced AD-associated pathology by reducing neuroinflammation through inhibition of NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome and inducing autophagy through activation of AMP-activated protein kinase (AMPK)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway. Thus, diet supplementation with OC-rich EVOO could provide beneficial effect to slow or halt the progression of AD.