Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy.

Defective mitophagy plays key roles in mitochondrial dysfunction, inflammation, and energy deprivation, and this defect can lead to synaptic loss and cognitive decline in Alzheimer's disease (AD). Although pharmacological enhancement of mitophagy has been found to ameliorate cognitive impairment in AD models, therapeutic strategies directly targeting this pathway remain limited. Ajugol, a bioactive iridoid glycoside isolated from Rehmannia glutinosa, has recently been identified as a potential metabolic regulator. In this study, we demonstrated that ajugol markedly alleviates mitochondrial damage and mitophagy impairment in 5 × FAD mice and HT22 cells. Mechanistically, ajugol upregulates BCL2-interacting protein 3 (BNIP3), which recruits LC3 to damaged mitochondria, thereby promoting mitophagosome formation and ultimately contributing to improved cognitive function. Notably, Bnip3 knockdown in hippocampal neurons abolished the beneficial effects of ajugol in 5 × FAD mice, exacerbating mitophagy defects and mitochondrial dysfunction, ultimately impairing cognitive performance. These findings highlight a previously unrecognized mechanism by which ajugol mitigates amyloid pathology, synaptic dysfunction, and cognitive decline in 5 × FAD mice and HT22 cells by enhancing BNIP3-mediated mitophagy, providing a potential therapeutic strategy for AD intervention.