Lignans from Schisandra chinensis (Turcz.) Baill ameliorates cognitive impairment in Alzheimer's disease and alleviates ferroptosis by activating the Nrf2/FPN1 signaling pathway and regulating iron levels

Abstract

Ethnopharmacological relevance: Schisandra chinensis (Turcz.) Baill (S. chinensis), first recorded in Shennong's Classic of the Materia Medica, is described as a "top grade medicine". As a traditional Chinese medicine of tonifying the kidneys and the brain, S. chinensis is widely used to treat diseases such as amnesia and dementia. Alzheimer's disease (AD) is a neurodegenerative disease, and ferroptosis is one of the essential causes of AD. Although previous studies have suggested that the lignans of S. chinensis (SCL) have neuroprotective effects, it is unclear whether SCL can alleviate AD pathology by inhibiting ferroptosis.

Aim of the study: To investigate the effect of SCL on AD caused by ferroptosis and its possible molecular mechanism.

Materials and methods: This study was based on SAMR1/SAMP8 mouse models along with Erastin-induced HT22 cell lines to examine the influence of SCL on ferroptosis in AD. The S. chinensis was extracted via 75% EtOH-H₂O and identified by HPLC/UPLC-QTOF-MS. MWM assessed spatial learning, while HE staining, biochemical detection, IHC, and WB analyzed AD pathology and iron metabolism. Mitochondrial changes were evaluated by TEM, and confocal imaging post-SCL treatment analyzed ROS, MMP, and Fe²⁺ levels in HT22 cells. IF determined the expression levels and localization of Nrf2 and FPN1. CETSA was deployed to study the interaction between SCL and Nrf2.

Results: Treatment with SCL mitigated cognitive dysfunction and reduced p-Tau as well as neuronal loss in AD model mice. Additionally, the administration of SCL alleviated oxidative stress and maintained relatively intact mitochondrial ridges and membranes, decreased TFR and DMT1 protein expression, and upregulated FTH1. Consistent with the in vivo results, SCL inhibited Erastin-induced ferroptosis in HT22 cells. SCL promoted Nrf2 nuclear translocation and upregulated FPN1, SLC7A11, and GPX4 protein expressions while decreasing FACL4. The improvement of ferroptosis by SCL was associated with the regulation of the Nrf2/FPN1 signaling pathway.

Conclusion: The novel discoveries of this study suggest that SCL can suppress ferroptosis in the brains of AD model mice and exerts a partial protective effect against Erastin-induced ferroptosis in HT22 cells, in which the Nrf2/FPN1 signaling pathway plays a crucial role.

Keywords: Alzheimer's disease; Ferroptosis; Lignans; Nrf2/FPN1; Schisandra chinensis (Turcz.) Baill.