Isoforsythiaside confers neuroprotection against Alzheimer’s disease by attenuating ferroptosis and neuroinflammation in vivo and in vitro

Abstract

Ferroptosis and neuroinflammation contribute to the development of Alzheimer's disease (AD). Isoforsythiaside (IFY) is a phenylethanoid glycoside isolated from the dried fruit of Forsythia suspensa (Thunb.) Vahl that has been confirmed to improve the memory and cognitive abilities of APP/PS1 mice in our previous study. The purpose of this study was to explore the anti-ferroptosis and anti-neuroinflammatory properties of IFY-mediated neuroprotection. In APP/PS1 mice, erastin-damaged HT22 cells, and LPS-exposed BV2 cells, the neuroprotective effects against ferroptosis and neuroinflammation were investigated using immunohistochemistry, label-free proteomics, western blot, ELISA, MTT, fluorescence, and TEM. IFY alleviated the expression levels of NO, IL-6, and IL-1β in LPS-exposed BV2 cells and improved the morphology of mitochondria in erastin-damaged HT22 cells. Additionally, IFY upregulated the expression levels of GPX4, FTH, FTL, p-GSK-3β, Nrf2, and NQO1, and downregulated the expression of TFR1, DMT1, p-Fyn, GFAP, p-IKKα+β, p-IκBα, p-NF-κB, and pro-inflammatory factors in the brains of APP/PS1 mice and erastin-damaged HT22 cells. In conclusion, IFY inhibits ferroptosis and neuroinflammation in erastin-damaged HT22 cells and APP/PS1 mice, at least partially by regulating the activation of Nrf2 and NF-κB signaling. IFY may prevent ferroptosis and neuroinflammation in AD and provide a new treatment strategy for AD.