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基于PINK1/Parkin信号通路研究细叶远志皂苷对AD模型小鼠脑组织线粒体自噬的影响
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| 篇名： | 基于PINK1/Parkin信号通路研究细叶远志皂苷对AD模型小鼠脑组织线粒体自噬的影响 |
| TITLE： | Study on the Effects of Tenuifolin on Brain Mitochondrial Autophagy in AD Model Mice Based on PINK 1/Parkin Signaling Pathway |
| 摘要： | 目的：探讨细叶远志皂苷（TEN）对阿尔茨海默病（AD）模型小鼠脑组织线粒体自噬的影响。方法：将50只雄性APP/PS1双转基因小鼠随机分为模型组、TEN中剂量+3-甲基腺嘌呤（3-MA）组[TEN40mg/（kg·d）+自噬抑制剂3-MA30mg/（kg·d）]和TEN低、中、高剂量组[20、40、80mg/（kg·d）]，每组10只；另将10只同系野生型小鼠作为正常对照组。各给药组小鼠灌胃相应药液，正常对照组和模型组小鼠灌胃0.3％羧甲基纤维素钠溶液，每天给药1次，给药体积为0.01mL/g，连续给药3个月。末次给药后，检测神经元内微管相关蛋白1轻链3（LC3）的阳性表达水平[以积分光密度（IOD）计]，脑组织线粒体中LC3、泛素结合蛋白p62、CathepsinD、Rab7、人第10号染色体缺失的磷酸酶及张力蛋白同源基因诱导的假定激酶1（PINK1）、E3泛素连接酶（Parkin）mRNA的表达量和LC3、p62、PINK1、Parkin蛋白的表达量。结果：与正常对照组比较，模型组小鼠神经元内LC3的IOD值和脑组织线粒体中LC3、p62、PINK1、ParkinmRNA及其蛋白的表达量均显著升高（P＜0.05或P＜0.01），CathepsinD、Rab7mRNA的表达量均显著降低（P＜0.05或P＜0.01）。与模型组比较，TEN低、中、高剂量组小鼠神经元内LC3的IOD值（除TEN低、中剂量组外）和脑组织线粒体中LC3、CathepsinD、Rab7、PINK1（除TEN低剂量组外）、Parkin（除TEN低剂量组外）mRNA的表达量以及LC3（除TEN中剂量组外）、PINK1（除TEN高剂量组显著降低外）、Parkin（除TEN低剂量组显著降低外）蛋白的表达量均显著升高（P＜0.05或P＜0.01），p62mRNA（除TEN低剂量组外）及其蛋白的表达量均显著降低（P＜0.05或P＜0.01）。与TEN中剂量组比较，TEN中剂量+3-MA组小鼠上述指标的变化均被显著抑制（P＜0.05或P＜0.01）。结论：TEN可通过激活PINK1/Parkin信号通路来诱导AD模型小鼠脑组织线粒体自噬，增强溶酶体功能。 |
| ABSTRACT： | OBJECTIVE：To investig ate the effects of tenuifolin （TEN）on brain mitochondrial autophagy in Aizheimer ’s disease（AD）model mice. METHODS ：Totally 50 male APP/PS1 double transgenic mice were randomly divided into model group，TEN medium-dose+ 3-MA group [TEN 40 mg/（kg·d）+autophagy inhibitor 3-MA 30 mg/（kg·d）] and TEN low-dose ， medium-dose and high-dose groups [ 20，40，80 mg/（kg·d）]，with 10 mice in each group. In addition ，10 wild-type homologous mice were included in normal control group. Administration groups were intragastrically given corresponding drug solution ；normal control group and model group were intragastrically given 0.3％ sodium carboxymethyl cellulose solution ，once a day ，0.01 mL/g， for consecutive 3 months. After last administration ，positive expression [measured by integrated optical density （IOD）] of microtubule associated protein 1 light chain 3（LC3）in neuron was detected ；mRNA expressions of LC3，ubiquitin-binding protein p62，Cathepsin D ，Rab7，phosphatase and tensin homolog deleted on chromosome ten gene-induced putative kinase 1（PINK1） and E 3 ligase（Parkin）as well as protein expressions of LC 3，p62，PINK1 and Parkin were detected in brain mitochondria. RESULTS：Compared with normal control group ，IOD value of LC 3 in neuron as well as mRNA and protein expressions of LC 3， p62，PINK1 and Parkin in brain mitochondria were all increased significantly in model group （P＜0.05 or P＜0.01），while mRNA expressions of Cathepsin D and Rab 7 were decreased significantly （P＜0.05 or P＜0.01）. Compared wit h model group ，IOD values of LC 3（except for TEN low-dose and medium-dose groups ） in neuron ，mRNA expressions of LC 3，Cathepsin D ，Rab7， PINK1（except for TEN low-dose group ）and Parkin （except for TEN low-dose group ） in brain mitochondria as well as protein expressions of LC 3 （except for TEN medium-dose group），PINK1（except fo r TEN high-dose group decreased significantly）and Parkin （except for TEN low-dose group decreased significantly ）were increased significantly in TEN low-dose ， medium-dose and high-dose groups （P＜0.05 or P＜0.01）；mRNA（except for TEN low-dose group ）and protein expressions of p62 were decreased significantly （P＜0.05 or P＜0.01）. Compared with TEN medium-dose group ，the changes of above indexes were inhibited significantly in TEN medium-dose + 3-MA group （P＜0.05 or P＜0.01）. CONCLUSIONS ：TEN can induce mitophagy in brain tissue of AD model mice by activating PINK 1/Parkin signaling pathway and improve lysosome function. |
| 期刊： | 2021年第32卷第22期 |
| 作者： | 陆晓华，金桂芳，余河汉，杨红 |
| AUTHORS： | LU Xiaohua ，JIN Guifang，YU Hehan ，YANG Hong |
| 关键字： | 细叶远志皂苷；阿尔茨海默病；PINK1/Parkin信号通路；线粒体自噬；APP/PS1双转基因小鼠 |
| KEYWORDS： | Tenuifolin；Alzheimer’s disease ；PINK1/Parkin signaling pathway ；Mitochondrial autophagy ；APP/PS1 double |
| 阅读数： | 332 次 |
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