Abstract
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-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 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.
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Acknowledgements
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 NotchΔE and Dr Johan Lundkvist (Karolinska Institutet) for the plasmid of Gal4-driven luciferase reporter gene, the plasmid of APP/CTFβ-GVP and NΔE-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).
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Supplementary information, Figure S1
DOR and MORDT but not MOR or DORMT enhances BACE and PS1 endocytic trafficking. (PDF 125 kb)
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The effect of NTI treatment on mice. (PDF 138 kb)
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Teng, L., Zhao, J., Wang, F. et al. A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis. Cell Res 20, 138–153 (2010). https://doi.org/10.1038/cr.2010.3
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DOI: https://doi.org/10.1038/cr.2010.3
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