Polygala Tenuifolia Willd. Ameliorates Neuronal Damage in Alzheimer's Disease Model Mice by Regulating Ferroptosis Through Modulation of the Nrf2/SLC7A11/GPX4 Axis.

This study aimed to explore the effects of Polygala-containing Formula (PCF) on ferroptosis and cognitive dysfunction in both Alzheimer’s disease (AD) mouse models and in cell-based experiments. A mouse model of AD was established in male mice using Aβ1-42. After successful model induction, mice were intraperitoneally injected with different dosages of PCF and continuously administered for 8 weeks. The Morris water maze test and Y maze test were used to assess the behavioral performance of mice, and brain tissues changes were assessed by hematoxylin eosin staining and immunohistochemistry. HT22 cells were treated with Aβ1-42. Cell viability was determined by MTT assay, and cytotoxicity was assessed by detecting LDH levels. Apoptosis was measured by assessing caspase-3/8/9 and flow cytometry analysis. Malondialdehyde, glutathione, iron levels, lipid peroxidation, expression of relevant proteins were determined. Aβ1-42 (15 µM) significantly decreased cell viability, whereas 25 or 50 µM PCF increased cell viability, decreased LDH release, inhibited apoptosis, and decreased caspase-3, caspase-8, and caspase-9 activity. In the mouse model, 20 mg/kg PCF improved AD-like behaviors, and inhibited the deposition of Aβ1-42, p-tau and 4-HNE in the brain. PCF inhibited Aβ1-42-induced ferroptosis in mice, decreased iron and ROS levels, increased GSH levels, and promoted GPX4 and FTH1 expression in both models. Erastin reversed the inhibitory effects of PCF on ferroptosis in HT22 cells. PCF modulated the Nrf2/SLC7A11/GPX4 axis by upregulating Nrf2, SLC7A11, and GPX4 protein expression. PCF exerts multifaceted protective effects against Aβ1-42-induced injury, suggesting a therapeutic strategy for AD.