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

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

Research output: Contribution to journalArticlepeer-review

270 Scopus citations

Abstract

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 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.

Original languageEnglish
Pages (from-to)1548-1562
Number of pages15
JournalCell Death and Differentiation
Volume28
Issue number5
DOIs
StatePublished - May 2021

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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