Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease.
Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer's disease.
复制标题
铁转运蛋白的缺失会通过促进阿尔茨海默病中的铁死亡而导致记忆障碍。
DOI：
10.1038/s41418-020-00685-9
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发表时间：
2021-05
影响因子：
12.4
通讯作者：
Zhu LQ
中科院分区：
文献类型：
--
作者：
Bao WD;Pang P;Zhou XT;Hu F;Xiong W;Chen K;Wang J;Wang F;Xie D;Hu YZ;Han ZT;Zhang HH;Wang WX;Nelson PT;Chen JG;Lu Y;Man HY;Liu D;Zhu LQ
铁稳态失调与阿尔茨海默病(AD)有关，过量的铁会加剧氧化损伤和认知缺陷。铁下垂是一种依赖于细胞内铁的非凋亡性细胞死亡形式。然而，铁性下垂在阿尔茨海默病发病机制中的作用仍不清楚。在这里，我们报告了铁门户蛋白1(FPN)，这是唯一已发现的哺乳动物非血红素铁输出蛋白，作为阿尔茨海默病小鼠模型和阿尔茨海默病患者在APPsWE/PS1dE9小鼠的大脑中下调。用NEX-CRE小鼠饲养Fpnfl/fl小鼠后，Fpnfl/fl小鼠大脑皮层和海马区主神经元FPN基因缺失，导致类AD海马区萎缩和记忆障碍。有趣的是，在Fpnfl/fl/Nexcre和AD小鼠中都观察到了典型的铁性下垂的形态和分子特征。对铁下垂相关RNA-SEQ数据的基因集浓缩分析(GSEA)表明，差异表达的基因在AD相关基因集中高度丰富。此外，在体内和体外，给予铁下垂的特异性抑制剂有效地减少了Aβ聚集引起的神经元死亡和记忆损伤。此外，修复FPN还可改善APPsWE/PS1dE9小鼠的铁性下垂和记忆障碍。我们的研究证明了FPN和铁性下垂在AD进展中的关键作用，从而为这种疾病提供了有希望的治疗方法。
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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
29
作者：
Drakesmith H;Nemeth E;Ganz T
通讯作者：
Ganz T
影响因子：
11
作者：
Ayton, Scott;Wang, Yamin;Bush, Ashley I.
通讯作者：
Bush, Ashley I.
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
82.9
作者：
Holcomb, L;Gordon, MN;Duff, K
通讯作者：
Duff, K