Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin.
Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Aβ catabolic enzyme Neprilysin.
复制标题
激活 AhR 通过上调内源性 AB 分解代谢酶脑啡肽酶缓解阿尔茨海默病模型小鼠的认知缺陷
作者：
Qian C;Yang C;Lu M;Bao J;Shen H;Deng B;Li S;Li W;Zhang M;Cao C
脑啡肽酶（Neprilysin，NEP）是β淀粉样蛋白（amyloid β，Aβ）的主要内源性分解代谢酶。先前的研究表明，在阿尔茨海默病动物模型中增加NEP表达具有改善作用。然而，调节NEP表达的潜在信号通路仍不清楚。芳香烃受体（AhR）是一种配体激活的细胞质受体和转录因子。近年来的研究表明，AhR在中枢神经系统（CNS）中发挥着重要作用，但其在调节NEP中的生理和病理作用尚不完全清楚。研究方法：采用Western blotting、免疫荧光、定量RT-PCR和酶活性测定等方法，在细胞模型（N2 a）和小鼠模型（APP/PS1）中验证AhR激动剂对NEP的影响。采用荧光素酶报告基因分析和染色质免疫沉淀（ChIP）分析研究AhR对NEP转录的调控作用。采用物体识别实验和Morris水迷宫实验评价小鼠的认知能力。结果如下：通过内源性配体L-犬尿氨酸（L-KN）或FICZ，或通过外源性配体地奥司明或吲哚-3-甲醇（I3 C）激活AhR可显著增加N2 a细胞和APP/PS1小鼠中的NEP表达和酶活性。我们还发现AhR是NEP的直接转录因子。地奥司明治疗有效地改善了APP/PS1转基因小鼠的认知障碍和记忆缺陷。通过敲除AhR或使用靶向AhR或NEP的小分子抑制剂，我们发现地奥司明通过激活AhR和增加NEP表达来增强Aβ降解。结论：这些结果表明，一种新的途径，调节神经元中的NEP的表达和AhR可能是一个潜在的治疗阿尔茨海默病的治疗靶点。
Rationale: Neprilysin (NEP) is a major endogenous catabolic enzyme of amyloid β (Aβ). Previous studies have suggested that increasing NEP expression in animal models of Alzheimer's disease had an ameliorative effect. However, the underlying signaling pathway that regulates NEP expression remains unclear. The aryl hydrocarbon receptor (AhR) is a ligand-activated cytoplasmic receptor and transcription factor. Recent studies have shown that AhR plays essential roles in the central nervous system (CNS), but its physiological and pathological roles in regulating NEP are not entirely known. Methods: Western blotting, immunofluorescence, quantitative RT-PCR and enzyme activity assay were used to verify the effects of AhR agonists on NEP in a cell model (N2a) and a mouse model (APP/PS1). Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were conducted to investigate the roles of AhR in regulating NEP transcription. Object recognition test and the Morris water maze task were performed to assess the cognitive capacity of the mice. Results: Activating AhR by the endogenous ligand L-Kynurenine (L-KN) or FICZ, or by the exogenous ligand diosmin or indole-3-carbinol (I3C) significantly increases NEP expression and enzyme activity in N2a cells and APP/PS1 mice. We also found that AhR is a direct transcription factor of NEP. Diosmin treatment effectively ameliorated the cognitive disorder and memory deficit of APP/PS1 transgenic mice. By knocking down AhR or using a small molecular inhibitor targeting AhR or NEP, we found that diosmin enhanced Aβ degradation through activated AhR and increased NEP expression. Conclusions: These results indicate a novel pathway for regulating NEP expression in neurons and that AhR may be a potential therapeutic target for the treatment of Alzheimer's disease.
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影响因子：
12.4
作者：
Cearley, CN;Wolfe, JH
通讯作者：
Wolfe, JH
影响因子：
3.5
作者：
Liu, Yinxing;Studzinski, Christa;Beckett, Tina;Murphy, M. Paul;Klein, Ronald L.;Hersh, Louis B.
通讯作者：
Hersh, Louis B.
DOI：
10.1093/brain/awt308
发表时间：
2014-02
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Henderson SJ;Andersson C;Narwal R;Janson J;Goldschmidt TJ;Appelkvist P;Bogstedt A;Steffen AC;Haupts U;Tebbe J;Freskgård PO;Jermutus L;Burrell M;Fowler SB;Webster CI
通讯作者：
Webster CI
影响因子：
14.8
作者：
Leger, Marianne;Quiedeville, Anne;Freret, Thomas
通讯作者：
Freret, Thomas
雌激素通过上调脑啡肽酶刺激β-淀粉样肽的降解
影响因子：
4.8
作者：
Liang, Kaiwei;Yang, Liuqing;Huang, Jian
通讯作者：
Huang, Jian