Dose-dependent evaluation of chronic oleocanthal on metabolic phenotypes and organ toxicity in 5xFAD mice

In Alzheimer's disease (AD), alterations in the basal metabolic rate (BMR) and energy expenditure, known as metabolic phenotyping, are present early in the disease, which progresses as the disease advances. The Mediterranean diet, including extra-virgin olive oil (EVOO), has been known to reduce AD risk. Oleocanthal (OC) is a major phenolic compound in EVOO. Previous research showed that OC reduced brain amyloid-β, tau hyperphosphorylation, neuroinflammation, and improved blood-brain barrier and memory functions in AD mouse models. In this work, we aimed to investigate the dose-dependent impact of chronic oral OC treatment on modulating metabolic phenotypes affected by AD and its toxicity in 5xFAD mice, an AD mouse model. 5xFAD mice were treated with OC for 3 months, starting at the ages of one (prevention mode, before the pathology hallmarks appear) and 6 months (treatment mode, after the pathology hallmarks appear). Findings demonstrated OC altered metabolic phenotypes in the 5-20 mg/kg dose range in both groups. Furthermore, OC proved not toxic except at 20 mg/kg, where hepatic toxicity is observed. In conclusion, these findings highlight the OC effect in rectifying metabolic phenotypes in AD. However, it limits the dose range in mice to 5 and 10 mg/kg despite exhibiting a favorable response in metabolic parameters due to observed hepatotoxicity with the 20 mg/kg.