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

Author:

Bao Wen-Dai,Pang Pei,Zhou Xiao-Ting,Hu Fan,Xiong Wan,Chen Kai,Wang Jing,Wang FudiORCID,Xie Dong,Hu Ya-Zhuo,Han Zhi-Tao,Zhang Hong-Hong,Wang Wang-XiaORCID,Nelson Peter T.,Chen Jian-Guo,Lu Youming,Man Heng-YeORCID,Liu Dan,Zhu Ling-QiangORCID

Abstract

AbstractIron 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 Fpnfl/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 Fpnfl/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.

Funder

National Natural Science Foundation of China

China Postdoctoral Science Foundation

The National Program for the Support of Top-Notch Young Professionals and Academic Frontier Youth Team of Huazhong University of Science and Technology

Publisher

Springer Science and Business Media LLC

Subject

Cell Biology,Molecular Biology

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