Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice
Yonggang Fan, Ri‐Le Ge, Hang Ren, Rong‐Jun Jia, Ting-Yao Wu, Xian-Fang Lei, Zheng Wu, Xiao-Bei Zhou, Zhan‐You Wang
Abstract
Increased astrocytic lactoferrin (Lf) expression was observed in the brains of elderly individuals and Alzheimer's disease (AD) patients. Our previous study revealed that astrocytic Lf overexpression improved cognitive capacity by facilitating Lf secretion to neurons to inhibit β-amyloid protein (Aβ) production in APP/PS1 mice. Here, we further discovered that astrocytic Lf overexpression inhibited neuronal loss by decreasing iron accumulation and increasing glutathione peroxidase 4 (GPX4) expression in neurons within APP/PS1 mice. Furthermore, human Lf (hLf) treatment inhibited ammonium ferric citrate (FAC)-induced ferroptosis by chelating intracellular iron. Additionally, machine learning analysis uncovered a correlation between Lf and GPX4. hLf treatment boosted low-density lipoprotein receptor-related protein 1 (LRP1) internalization and facilitated its interaction with heat shock cognate 70 (HSC70), thereby inhibiting HSC70 binds to GPX4, and eventually attenuating GPX4 degradation and FAC-induced ferroptosis. Overall, astrocytic Lf overexpression inhibited neuronal ferroptosis through two pathways: reducing intracellular iron accumulation and promoting GPX4 expression via inhibiting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation. Hence, upregulating astrocytic Lf expression is a promising strategy for combating AD. Overexpression of Lf in astrocytes facilitates Lf secretion to neurons by targeting LRP1, which inhibits neuronal ferroptosis by two distinct pathways: (1) reducing iron accumulation by chelating intracellular iron; (2) promoting the interaction between HSC70 and LRP1 by boosting LRP1 internalization, and subsequently inhibiting CMA-mediated GPX4 degradation, which ultimately halts ROS generation and ferroptosis. • Astrocytic lactoferrin overexpression inhibits neuronal ferroptosis in APP/PS1 mouse brains. • LRP1 regulates GPX4 expression via a chaperone-mediated autophagy pathway. • Lactoferrin inhibits neuronal ferroptosis via chelating iron and upregulating GPX4 expression.