GLUCAGON-LIKE PEPTIDE-1 REGULATES MITOCHONDRIAL BIOGENESIS AND TAU PHOSPHORYLATION AGAINST ADVANCED GLYCATION END PRODUCT-INDUCED NEURONAL INSULT: STUDIES IN VIVO AND IN VITRO
GLUCAGON-LIKE PEPTIDE-1 REGULATES MITOCHONDRIAL BIOGENESIS AND TAU PHOSPHORYLATION AGAINST ADVANCED GLYCATION END PRODUCT-INDUCED NEURONAL INSULT: STUDIES IN VIVO AND IN VITRO
复制标题
胰高血糖素样肽-1 调节线粒体生物发生和 Tau 磷酸化，对抗高级糖化终产物引起的神经元损伤：体内和体外研究
DOI：
10.1016/j.neuroscience.2015.05.023
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发表时间：
2015-08-06
期刊：
影响因子：
3.3
通讯作者：
Gao, X. -D.
中科院分区：
文献类型：
--
作者：
An, F. -M.;Chen, S.;Gao, X. -D.
我们前期的研究已经证明，开发用于治疗2型糖尿病的胰高血糖素样肽-1（GLP-1）在糖尿病相关阿尔茨海默病（AD）体外模型中对晚期糖基化终产物（AGE）诱导的神经元损伤具有显著的神经保护作用。然而，其分子机制仍有待阐明，目前尚不清楚GLP-1受体是否介导了体内对AGE诱导的AD样变化的下调作用。本研究旨在探讨GLP-1受体激动剂（GLP-1 RA）对AGE依赖性信号通路的影响及其机制。在这项研究中，我们证明了GLP-1 RA可以抑制氧化应激和修复线粒体损伤，除了减少tau蛋白过度磷酸化与AGEs处理的PC 12细胞。重要的是，我们首次观察到AGEs在循环系统中可以诱导tau蛋白过度磷酸化后，我们注射AGEs（1 μ g/kg体重）到小鼠尾静脉。我们发现GLP-1 RA在体内除了通过下调糖原合成酶激酶3 β（GSK-3 β）的活性直接逆转tau蛋白过度磷酸化外，还可以通过调节过氧化物酶体增殖物激活受体γ共激活因子1 α（PGC-1 α）信号通路促进线粒体生物合成和抗氧化系统。总之，我们的研究结果表明，GLP-1 RA通过调节GSK-3 β和PGC-1 α两种协同信号通路保护神经元免受AGE诱导的tau过度磷酸化。(C)2015年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Our previous study has proved that glucagon-like peptide-1 (GLP-1), which is developed to treat type 2 diabetes, has a significant effect on neuroprotection against advanced glycation end product (AGE)-induced neuronal insult in vitro models of diabetes-related Alzheimer's disease (AD). However, the molecular mechanisms remain to be elucidated and it is not clear whether GLP-1 receptor mediates the down-regulation effects on AGE-induced AD-like changes in vivo. This study aims to explore the effect and mechanisms of GLP-1 receptor agonists (GLP-1RA) against the AGE-dependent signaling pathway both in vitro and in vivo. In this study, we demonstrated that GLP-1RA could inhibit oxidative stress and repair mitochondrial damage in addition to decreasing tau hyperphosphorylation in PC12 cells treated with AGEs. Importantly, we first observed AGEs in the circulatory system could induce tau hyperphosphorylation after we injected AGEs (1 mu g/kg bodyweight) into the mice tail vein. We found GLP-1RA could promote mitochondrial biogenesis and antioxidant system via regulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) signaling pathway in vivo besides down-regulating the activity of glycogen synthase kinase 3 beta (GSK-3 beta) to reverse tau hyperphosphorylation directly. Collectively, our results suggest that GLP-1RA protects neurons against AGE-induced tau hyperphosphorylation via regulating GSK-3 beta and PGC-1 alpha two cooperative signaling pathways. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.