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.
|Number of pages||15|
|Journal||Cell Death and Differentiation|
|State||Published - May 2021|
Bibliographical noteFunding Information:
Acknowledgements We thank Dr. NC Andrews for the Fpn-floxed mice, Dr Z Qiu for the NEX-Cre mice, and all of the patients who donated tissue for this research. This work was supported partially by the National Key Research and Development Program of China (Grant No. 2019YFE0121200), the National Natural Science Foundation of China (32070960, 82030032, 81829002, 81961128005, 81871108, 81700789, 31330036, and 31530034), Top-Notch Young Talents Program of China of 2014 and Academic Frontier Youth Team of Huazhong University of Science and Technology (to Ling-Qiang Zhu), the China Postdoctoral Science Foundation (2017M612467) (to WD-B), and the National Key Research and Development Program (2018YFA0507802) (to FW).
General Hospital and Chinese PLA Medical Academy. The patient information was described previously . Cortical tissues (temporal pole) from the brains of nondementia control subjects and AD cases, based on neuropathological diagnosis in Supplementary Fig. S1D (7CON vs 7AD), were obtained from the University of Kentucky Alzheimer’s Disease Center (supported by NIH/NIA P30 AG028383) autopsy cohort. Detailed patient information is listed in Supplementary Table 1. Informed consents were obtained from all the subjects. The present study was approved by the ethics committee of Tongji Medical College (Wuhan, China).
© 2021, The Author(s).
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology