A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis
A GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis
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DOI：
10.1038/cr.2010.3
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发表时间：
2010-02-01
期刊：
影响因子：
44.1
通讯作者：
Pei, Gang
中科院分区：
文献类型：
--
作者：
Teng, Lin;Zhao, Jian;Pei, Gang
β 位点 APP 裂解酶 (BACE) 和/或 γ 分泌酶的失调会导致 β 淀粉样蛋白的异常产生。肽（Aβ）并导致阿尔茨海默病（AD）的病因学。由于这些分泌酶介导多种蛋白质的蛋白水解加工，因此由于不可避免的不良副作用，通过分泌酶抑制剂治疗AD几乎没有取得成功。因此，阐明这些分泌酶的调节机制非常重要。在这里，我们证明 δ-阿片受体 (DOR) 促进 Aβ 的加工。 BACE1 和 γ 分泌酶的前体蛋白 (APP)，但不包括 Notch、N-钙粘蛋白或 APLP。进一步研究表明，DOR 与 BACE1 和 γ-分泌酶形成复合物，DOR 的激活介导 APP 内切蛋白水解的分泌酶/受体复合物的共内吞分选。受体功能障碍会阻碍 BACE1 和 γ 分泌酶的内吞作用，从而阻碍 Aβ 的产生。一致地，DOR的敲低或拮抗可降低分泌酶活性并改善Aβ病理学和Aβ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 Aβ 分泌酶生成的特异性，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针对 AD 的新策略，并且可能具有更少的副作用。
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.