中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
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.

入库方式: OAI收割

来源:上海生物化学与细胞生物学研究所

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