Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Cell Res. 2010 Feb;20(2):138-53. doi: 10.1038/cr.2010.3. Epub 2010 Jan 12.
Dysregulation of beta-site APP-cleaving enzyme (BACE) and/or gamma-secretase leads to anomalous production of amyloid-beta peptide (Abeta) 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 Abeta 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 Abeta. Consistently, knockdown or antagonization of DOR reduces secretase activities and ameliorates Abeta pathology and Abeta-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 Abeta 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.
β-位点 APP 裂解酶（BACE）和/或γ-分泌酶的失调导致淀粉样β肽（Abeta）的异常产生，并有助于阿尔茨海默病（AD）的病因。由于这些分泌酶介导许多蛋白质的蛋白水解加工，因此通过分泌酶抑制剂治疗 AD 几乎没有取得成功，因为不可避免地会产生不良副作用。因此，揭示这些分泌酶的调节机制非常重要。在这里，我们表明 δ-阿片受体（DOR）促进 BACE1 和 γ-分泌酶对 Abeta 前体蛋白（APP）的加工，但不促进 Notch、N-钙粘蛋白或 APLP 的加工。进一步的研究表明，DOR 与 BACE1 和 γ-分泌酶形成复合物，DOR 的激活介导了该复合物与 APP 内肽酶切割的共内吞分选。受体功能障碍会延迟 BACE1 和 γ-分泌酶的内吞作用，从而减少 Abeta 的产生。一致地，DOR 的敲低或拮抗作用降低了酶的活性，并改善了 Abeta 病理学和 Abeta 依赖性行为缺陷，但不影响 AD 模型小鼠中 Notch、N-钙粘蛋白或 APLP 的加工。我们的研究不仅揭示了 DOR/分泌酶复合物形成的分子机制，该复合物调节了分泌酶对 Abeta 产生的特异性，而且还表明干预 GPCR/分泌酶复合物的形成或运输可能会导致一种新的 AD 治疗策略，潜在的副作用更少。
