上海生命科学院生化与细胞研究所分子细胞生物学实验室，复旦大学药理研究中心，同济大学生命科学与技术学院的科学家在Cell Research在线版上发表阿尔茨海默病的{zx1}研究进展文章。

老年痴呆症的主要病理学特征为大脑内神经细胞表面由于异常的淀粉样蛋白斑沉淀而呈现的老年斑（senile plaque），神经纤维丝缠结，以及神经元死亡。淀粉样蛋白斑主要是由细胞内异常产生的大量β淀粉样蛋白（Aβ）在细胞外积聚形成的。目前广为接受的“Aβ假说”认为细胞外异常沉积的β淀粉样蛋白通过一系列细胞级联反应（包括自由基反应、线粒体氧化损伤和炎症反应等），直接或间接地作用于神经元和胶质细胞，最终导致神经元功能异常或死亡，引起认知障碍。

老年痴呆症（Alzheimer's disease）是发生在早老及老年期以进行性痴呆和精神行为异常为主的xxxx系统退行性疾病。老年痴呆症在老年人死因中仅次于心脏病、肿瘤和，占第四位。随着中国社会逐渐迈向老龄化，如何对包括老年痴呆症在内的一系列神经退行性疾病进行有效地预防和早期xx直接关系到我国的人口质量和全民健康水平，已成为我国面临的一项关系到国家人口与健康的战略问题。

研究认为抑制β-AR与γ分泌酶将有效抑制淀粉样蛋白的沉积，理论上可以减缓或是停止阿尔茨海默病的发展进程。然而，遗憾的是，这些酶不仅参与阿尔茨海默病的病理过程，同时还调节其他信号，如Notch信号和钙粘蛋白，如果抑制这两种酶将导致其他功能混乱。

院士研究小组发现β与γ－分泌酶活性具有同时促进Aβ的生成。这种增强作用与β-AR和早老素－1的相关性有关，并需要β-AR的xx剂诱导的细胞内吞及随后的γ－分泌酶进入次级包涵体和溶酶体，那里是Aβ生成的地方。

研究小组发现β-AR与γ－分泌酶需与δ阿片受体形成复合物，在共同促进淀粉样蛋白的生成。研究发现使用抵抗δ阿片受体的xxnaltrindole可有效地缓解淀粉样蛋白的生成，在此过程中，没有出现副作用，研究者认为，这将是阿尔茨海默病的一个潜在xx靶位。（Bioon.com）

生物谷推荐原始出处：

Cell Research advance online publication 12 January 2010; doi: 10.1038/cr.2010.3

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

Lin Teng1, Jian Zhao1, Feifei Wang2, Lan Ma2 and Gang Pei1,3

1Laboratory 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
2Pharmacology Research Center, Shanghai Medical School, Fudan University, Shanghai 200032, China
3School of Life Science and Technology, Tongji University, Shanghai 200092, China

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.