A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis  

作　　者：Lin Teng Jian Zhao Feifei Wang Lan Ma Gang Pei 

机构地区：[1]Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China [2]Pharmacology Research Center, Shanghai Medical School, Fudan University, Shanghai 200032, China [3]School of Life Science and Technology, Tongji University, Shanghai 200092, China

出　　处：《Cell Research》2010年第2期138-153,共16页细胞研究（英文版）

基　　金：Supplementary information is linked to the online version of the paper on the Cell Research website.Acknowledgments We thank Dr David Westaway （University of Alberta） for TgCRND8 mice, Dr David Baltimore （California Institute of Technology） for lentiviral constructs, Dr Raphael Kopan （Washington University） for the plasmid of myc-tagged NotchAE and Dr Johan Lundkvist （Karolinska Institutet） for the plasmid of Gal4-driven luciferase reporter gene, the plasmid of APP/CTFI3-GVP and NAE-GVP. We appreciate Shunmei Xin, Shan Chen and Xianglu Zeng for their technical assistance. We thank all members of the lab for sharing reagents and advice. This research was supported by the Ministry of Science and Technology （2009ZX09103-684）, the National Natural Science Foundation of China （30621091, 30625014, 30623003, 30871285 and 90713047）, the Shanghai Municipal Commission for Science and Technology （07PJ14099 and 09JC1416400）, and the Chinese Academy of Sciences （2007KIP204）.

摘　　要：Dysregulation of β-site APP-cleaving enzyme （BACE） and/or γ-secretase leads to anomalous production of amyloid-β peptide （Aβ） 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 δ-opioid receptor （DOR） promotes the processing of Aβ precursor protein （APP） by BACE1 and γ-secretase, but not that of Notch, N-cadherin or APLP. Further investigation reveals that DOR forms a complex with BACE1 and γ-seeretase, 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 γ-secretase and thus the production of Aβ Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Aβ pathology and Aβ-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 Aβ 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.

关 键 词：G protein-coupled receptor Alzheimer＇s disease BACE Γ-SECRETASE Notch 

分 类 号：Q959.215[生物学—动物学] TP393.4[自动化与计算机技术—计算机应用技术]