Hydroxytyrosol Acetate Improves the Cognitive Function of APP/PS1 Transgenic Mice in ERβ-dependent Manner

Scope: Alzheimer's disease (AD) is the most prevalent form of dementia in the aging population; however, no effective therapy has been established. It has been previously demonstrated that daily intake of hydroxytyrosol (HT), a polyphenol in olive oil, at a daily dietary level mildly improves cognition in AD mice. In the present study, HT acetate (HT-ac), which is a natural derivative of HT in olive oil that exhibits better bioactivity than HT improves cognition. Methods and Results: HT-ac to APP/PS1 is orally administered to transgenic mice and used Aβ-treated neuronal cultures to explore the neuroprotective effects of HT-ac in preventing AD progression. It is found that HT-ac remarkably improved the escape latency, escape distance, and the number of platform crossings of AD mice in the water maze test by ameliorating neuronal apoptosis and decreasing inflammatory cytokine levels. It is further demonstrated that HT-ac stimulated the transcription of ERβ and enhanced neuronal viability and electrophysiological activity in primary neurons but that these beneficial effects of HT-ac are abolished upon ERβ deficiency. Conclusions: This study suggests that as the bioactive component of olive oil, HT-ac is a promising neuroprotective nutrient that may be used to alleviate AD-related cognitive dysfunction.