Iron dysregulates APP processing accompanying with sAPP alpha cellular retention and beta-secretase inhibition in rat cortical neurons
文献类型：期刊论文
| 作者 | Chen, Yu-ting1,3; Chen, Wu-yan1; Huang, Xiao-tian1; Xu, Ye-chun1 ; Zhang, Hai-yan1,2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2018-02 |
| 卷号 | 39期号:2页码:177-183 |
| 关键词 | iron neurons amyloid precursor protein sAPP alpha beta-amyloid beta-secretase Alzheimer's disease |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2017.113 |
| 文献子类 | Article |
| 英文摘要 | Amyloid precursor protein (APP) and iron both play pivotal roles in the central nervous system, but whether and how iron influences the processing of endogenous APP in neurons remain unclear. Here, we investigated the regulatory effects and underlying mechanisms of iron on non-amyloidogenic and amyloidogenic processing of APP in rat primary cortical neurons. Treatment of the neurons with ferric ammonium citrate (FAC, 100 mu mol/L) markedly facilitated the non-amyloidogenic processing of APP, as evidenced by a robust increase in alpha-secretase-derived carboxy-terminal fragment alpha (CTF alpha). Furthermore, the distribution of sAPP alpha was altered after iron treatment, and sAPP alpha remained in the cellular lysates instead of being secreted into the extracellular milieu. Moreover, the levels of APP amyloidogenic products, including sAPP beta and A beta were both decreased. We further revealed that FAC did not alter the expression of beta-secretase, but significantly suppressed its enzymatic activity in iron-treated neurons. In a cell-free beta-secretase activity assay, FAC dose-dependently inhibited the activity of purified beta-secretase with an IC50 value of 21.67 mu mol/L. Our data provide the first evidence that iron overload alters the neuronal sAPP alpha distribution and directly inhibits beta-secretase activity. These findings shed light on the regulatory mechanism of bio-metals on APP processing. |
| WOS关键词 | AMYLOID PRECURSOR PROTEIN ; INDUCED OXIDATIVE STRESS ; ALZHEIMERS-DISEASE ; A-BETA ; CEREBROSPINAL-FLUID ; ENDOTHELIAL-CELLS ; IN-VIVO ; BRAIN ; PEPTIDE ; ACCUMULATION |
| 资助项目 | National Natural Science Foundation of China[81522045] ; National Natural Science Foundation of China[31400932] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6163683 |
| WOS记录号 | WOS:000423868000003 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279935]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药理学第二研究室 |
| 通讯作者 | Xu, Ye-chun; Zhang, Hai-yan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Yu-ting,Chen, Wu-yan,Huang, Xiao-tian,et al. Iron dysregulates APP processing accompanying with sAPP alpha cellular retention and beta-secretase inhibition in rat cortical neurons[J]. ACTA PHARMACOLOGICA SINICA,2018,39(2):177-183. |
| APA | Chen, Yu-ting,Chen, Wu-yan,Huang, Xiao-tian,Xu, Ye-chun,&Zhang, Hai-yan.(2018).Iron dysregulates APP processing accompanying with sAPP alpha cellular retention and beta-secretase inhibition in rat cortical neurons.ACTA PHARMACOLOGICA SINICA,39(2),177-183. |
| MLA | Chen, Yu-ting,et al."Iron dysregulates APP processing accompanying with sAPP alpha cellular retention and beta-secretase inhibition in rat cortical neurons".ACTA PHARMACOLOGICA SINICA 39.2(2018):177-183. |
入库方式： OAI收割
来源：上海药物研究所
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