Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

• Published in: Cell death and differentiation Vol. 28; no. 5; pp. 1548 - 1562
• Main Authors: Bao, Wen-Dai, Pang, Pei, Zhou, Xiao-Ting, Hu, Fan, Xiong, Wan, Chen, Kai, Wang, Jing, Wang, Fudi, Xie, Dong, Hu, Ya-Zhuo, Han, Zhi-Tao, Zhang, Hong-Hong, Wang, Wang-Xia, Nelson, Peter T., Chen, Jian-Guo, Lu, Youming, Man, Heng-Ye, Liu, Dan, Zhu, Ling-Qiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2021; Nature Publishing Group
• Subjects: 13/1; 13/105; 13/89; 13/95; 14/19; 14/28; 38/22; 38/77; 38/90; 59/57; 631/378/2611; 631/443/7; 64/110; 64/60; 82/29; 82/51; Alzheimer Disease - genetics; Alzheimer's disease; Animals; Apoptosis; Atrophy; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Cognitive ability; Disease Models, Animal; Ferroptosis; Ferroptosis - physiology; Gene set enrichment analysis; Hippocampus; Homeostasis; Humans; Iron; Life Sciences; Memory; Memory Disorders - genetics; Mice; Neocortex; Neurodegenerative diseases; Physical characteristics; Stem Cells
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-020-00685-9

Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpn fl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpn fl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.