Schisandrin B ameliorates Alzheimer's disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal damage, with poor prognosis and limited therapeutic options. Inhibition of neuronal ferroptosis has shown promise as a potential treatment for AD. Schisandrin B (Sch B), a major active component of Schisandra chinensis, exhibits potential neuroprotective effects. However, whether Sch B inhibits neuronal ferroptosis remains unclear.

Purpose: To investigate the mechanisms underlying the effects of Sch B on the GSK3β/Nrf2/GPX4 and FSP1 signaling pathways, which are the suppression of neuronal ferroptosis and the potential therapeutic intervention in AD.

Methods: We employed the 3 × Tg mouse model in vivo, and utilized the erastin-induced ferroptosis model in SH-SY5Y/APP695swe cells in vitro. Nissl staining was conducted to facilitate histopathological assessment. Assessment of neuronal ferroptosis was performed utilizing a lipid peroxidation and ferroptosis marker assay kit. Furthermore, bioinformatic analysis was executed with the application of the GEO database. Immunofluorescence and Western blot analyses were performed to quantify protein expression levels within the cellular context. ELISA was utilized to determine cytokine concentrations within the supernatant of cell cultures. RT-PCR was executed to evaluate mRNA expression levels.

Results: Sch B suppresses the activation of GSK3β, modulating the Nrf2/GPX4 signaling pathway and consequently inhibiting ferroptosis in neurons, which results in amelioration of cognitive impairment and pathological damage in 3 × Tg mice. Sch B also inhibits GSK3β activation, thereby modulating the Nrf2/GPX4 signaling pathway to prevent erastin-induced ferroptosis in SH-SY5Y695swe cells in vitro. Furthermore, Sch B modulates FSP1, enhancing its synergistic interaction with the GSK3β/Nrf2/GPX4 pathway to suppress neuronal ferroptosis. Sch B can also inhibit TNF-α release from neurons undergoing ferroptosis, thus impeding the activation of M1-type microglia, suggesting a multifaceted neuroprotective strategy against neuroinflammatory processes.

Conclusion: Sch B modulates the GSK3β/Nrf2/GPX4 pathway in conjunction with FSP1 to inhibit neuronal ferroptosis and the subsequent microglial M1 polarization mediated by neuronal ferroptosis, thereby improving cognitive impairment and pathological damage in AD.

Keywords: Alzheimer's disease; FSP1; Ferroptosis; GSK3β; Polarization of microglia; Schisandrin B.