Oleuropein and hydroxytyrosol enhance mitochondrial function and biogenesis in SH-SY5Y cells through estrogen-like mechanisms

Age-related hormonal and metabolic changes critically increase vulnerability of neurons to neurodegeneration and cognitive decline. Estrogens are known to support neuronal survival, synaptic plasticity, and mitochondrial function, yet hormone replacement therapies have shown inconsistent neuroprotective outcomes. Safe alternatives are therefore highly desirable. In this study, we characterize Oleuropein aglycone (OleA) and hydroxytyrosol (HT), two of the main bioactive phenolic compounds found in extra virgin olive oil (EVOO), as multitarget neuromodulators with estrogen-like and neuroprotective potential. Unlike most studies on phytoestrogens, which have focused on single pathways such as estrogen receptor activation, our findings reveal a broader spectrum of actions. OleA and HT simultaneously modulate ER beta and IGF1R signaling, regulate Ca2+ dynamics through ryanodine, AMPA, and NMDA receptors, remodel the neuronal lipidome, and promote mitochondrial biogenesis and metabolic efficiency. Moreover, they influence amyloid-binding alcohol dehydrogenase (ABAD) expression, a mitochondrial target implicated in Alzheimer's disease. By converging on receptor signaling, lipid metabolism, and mitochondrial function, these compounds provide a systems-level perspective on neuronal protection. This multitarget activity, which mimics estrogen-like signaling, positions the investigated EVOO-derived phenolic compounds as safe dietary agents to counteract the neuronal decline associated with estrogen loss during ageing.