Bazi Bushen Capsule Rescues Menopausal Obesity-Induced Cognitive Impairment

摘要

Objective: Menopausal obesity significantly increases the risk of Alzheimer's disease（AD）, yet effective therapeutic strategies remain limited. Bazi Bushen capsule（BZBS）, a compound formulation used in traditional Chinese medicine, has shown clinical benefits in alleviating fatigue and forgetfulness; however, its mechanism of action in menopausal obesity-related AD has not been elucidated. This study aimed to investigate the effect of BZBS on AD-like cognitive impairment in ovariectomized high-fat diet-fed（OXHF） mice and to explore the underlying molecular mechanisms. Methods: An OXHF mouse model was established to evaluate the neuroprotective effects of BZBS. Cognitive functions were assessed using the Barnes maze, novel object recognition test, and nesting behavior analysis. Hippocampal mitochondrial ultrastructure was examined by transmission electron microscopy, and mitochondrial function was evaluated by measuring reactive oxygen species（ROS）, glutathione（GSH）, and ATP levels. Theta rhythm integrity was assessed via in vivo electrophysiology. Mechanistic insights were obtained through bioinformatic network analysis and validated by molecular biology techniques. Results: BZBS treatment significantly ameliorated OXHF-induced spatial and episodic memory deficits. It alleviated mitochondrial damage, including cristae swelling and loss, suppressed ROS overproduction, and restored GSH content and ATP synthesis in the hippocampus. Mechanistically, BZBS activated the NAMPT-NAD⁺-SIRT1 and PGC-1α-SIRT3 pathways, which were impaired in OXHF mice. These effects were abolished by AAV-mediated overexpression of miR-23a. Bioinformatic analysis suggested that BZBS inhibits the expression of aryl hydrocarbon receptor（AhR）, a transcriptional regulator of miR-23a. Administration of the AhR-specific agonist Kyn significantly counteracted BZBS-mediated pathway activation, and abolished the protective effects of BZBS on cognitive decline and theta rhythm deterioration. Conclusion: TThis study identifies AhR as a key molecular switch through which BZBS improves mitochondrial bioenergetics and cognitive function in OXHF mice via the miR-23a-SIRT axis.

关键词

Bazi Bushen capsule / AhR-miR-23a axis / mitochondrial dysfunction / theta oscillations / cognitive decline