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

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 rema...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166828/
https://www.ncbi.nlm.nih.gov/pubmed/33398092
http://dx.doi.org/10.1038/s41418-020-00685-9
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author 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
author_facet 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
author_sort Bao, Wen-Dai
collection PubMed
description 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.
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spelling pubmed-81668282021-06-15 Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease 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 Cell Death Differ Article 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. Nature Publishing Group UK 2021-01-04 2021-05 /pmc/articles/PMC8166828/ /pubmed/33398092 http://dx.doi.org/10.1038/s41418-020-00685-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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
Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
title Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
title_full Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
title_fullStr Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
title_full_unstemmed Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
title_short Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease
title_sort loss of ferroportin induces memory impairment by promoting ferroptosis in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166828/
https://www.ncbi.nlm.nih.gov/pubmed/33398092
http://dx.doi.org/10.1038/s41418-020-00685-9
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