A GPCR/secretase complex regulates beta- and gamma-secretase specificity for A beta production and contributes to AD pathogenesis
文献类型：期刊论文
| 作者 | Teng, L; Zhao, J; Wang, FF; Ma, L; Pei, G |
| 刊名 | CELL RESEARCH
 |
| 出版日期 | 2010 |
| 卷号 | 20期号:2页码:138-153 |
| 关键词 | G protein-coupled receptor Alzheimer's disease BACE gamma-secretase Notch |
| 通讯作者 | Pei, G (reprint author), Chinese Acad Sci, Mol Cell Biol Lab, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China.,jzhao@sibs.ac.cn ; gpei@sibs.ac.cn |
| 英文摘要 | Dysregulation of beta-site APP-cleaving enzyme (BACE) and/or gamma-secretase leads to anomalous production of amyloid-beta. peptide (A beta) and contributes to the etiology of Alzheimer's disease (AD). Since these secretases mediate proteolytic processing of numerous proteins, little success has been achieved to treat AD by secretase inhibitors because of inevitable undesired side effects. Thus, it is of importance to unravel the regulatory mechanisms of these secretases. Here, we show that delta-opioid receptor (DOR) promotes the processing of A beta. precursor protein (APP) by BACE1 and gamma-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and gamma-secretase, and activation of DOR mediates the co-endocytic sorting of the secretases/receptor complex for APP endoproteolysis. Dysfunction of the receptor retards the endocytosis of BACE1 and gamma-secretase and thus the production of A beta. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates A beta pathology and A beta-dependent behavioral deficits, but does not affect the processing of Notch, N-cadherin or APLP in AD model mice. Our study not only uncovers a molecular mechanism for the formation of a DOR/secretase complex that regulates the specificity of secretase for A beta production but also suggests that intervention of either formation or trafficking of the GPCR/secretase complex could lead to a new strategy against AD, potentially with fewer side effects. |
| 学科主题 | Cell Biology |
| 类目[WOS] | Cell Biology |
| 关键词[WOS] | AMYLOID PRECURSOR PROTEIN ; DELTA-OPIOID RECEPTOR ; TRANSGENIC MOUSE MODEL ; ALZHEIMERS-DISEASE ; INTRACELLULAR DOMAIN ; CONVERTING ENZYME ; PLAQUE-FORMATION ; SENILE DEMENTIA ; HUMAN BRAIN ; MU |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000275816100006 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/956]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Teng, L,Zhao, J,Wang, FF,et al. A GPCR/secretase complex regulates beta- and gamma-secretase specificity for A beta production and contributes to AD pathogenesis[J]. CELL RESEARCH,2010,20(2):138-153. |
| APA | Teng, L,Zhao, J,Wang, FF,Ma, L,&Pei, G.(2010).A GPCR/secretase complex regulates beta- and gamma-secretase specificity for A beta production and contributes to AD pathogenesis.CELL RESEARCH,20(2),138-153. |
| MLA | Teng, L,et al."A GPCR/secretase complex regulates beta- and gamma-secretase specificity for A beta production and contributes to AD pathogenesis".CELL RESEARCH 20.2(2010):138-153. |
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