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线粒体自噬在铝暴露大鼠认知障碍中的作用

The role of mitophagy in cognitive impairment in aluminum-exposed rats

    摘要
  • 摘要:
    目的 观察亚慢性铝暴露对大鼠海马线粒体自噬PTEN诱导激酶（PINK1）/E3泛素连接酶（Parkin）途径微管相关蛋白1轻链3B（LC3B）、选择性自噬接头蛋白62（P62）和细胞色素c氧化酶IV（COXIV）表达的影响，探讨铝暴露是否通过线粒体自噬PINK1/Parkin途径LC3B/P62/COXIV通路影响认知障碍的具体机制。
    方法 选取32只6周龄 SPF级的健康雄性SD大鼠，体重（190±20）g，按照体重随机分为4组：对照、低剂量（10 µmol/kg）、中剂量（20 µmol/kg）和高剂量组（40 µmol/kg），每组8只。动物染毒模型采用麦芽酚铝腹腔注射90 d。染毒完毕后，通过Morris水迷宫行为学实验测定大鼠学习记忆能力，通过冰冻切片测定大鼠大脑皮层活性氧（ROS）表达水平，通过免疫印迹法（WB）检测大鼠海马组织中PINK1、Parkin、LC3B、P62、COXIV蛋白的表达。
    结果 Morris水迷宫定位巡航实验的第3、4、5天，各组大鼠逃避潜伏期随着染毒剂量的增加逐渐延长（P<0.05），第6天，高剂量组较对照组和低中剂量组穿越平台及平台象限的次数均有所减少（P<0.05）。各组随着染毒剂量的升高，大鼠大脑皮层ROS水平逐渐增加（P<0.05），谷胱甘肽过氧化物酶（GSH-Px）含量逐渐减少（P<0.05）。各组大鼠大脑海马组织中PINK1、Parkin、LC3B的相对表达水平随着染毒剂量的增加逐渐上升（P<0.05），P62、COXIV的相对表达水平随着染毒剂量的增加逐渐下降（P<0.05）。
    结论 亚慢性铝暴露可以损伤大鼠的学习记忆功能，并激活PINK1/Parkin途径LC3B/P62/COXIV通路，诱导线粒体自噬。

     

    Abstract:
    Objective To observe the effects of subchronic aluminum exposure on the expression of PTEN-induced kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) pathway microtubule-associated protein 1 light chain 3B (LC3B), selective autophagy receptor protein 62 (P62), and cytochrome c oxidase IV (COXIV) in rat hippocampal mitochondria, and to explore the specific mechanism by which aluminum exposure affects cognitive impairment through the mitophagy PINK1/Parkin pathway LC3B/P62/COXIV pathway.
    Methods Thirty-two 6-week-old healthy male Sprague-Dawley (SD) rats of SPF grade, weighing (190±20) g, were randomly divided into four groups according to their body weight: control, low-dose (10 µmol/kg), medium-dose (20 µmol/kg), and high-dose (40 µmol/kg) groups, with 8 rats in each group. The animal intoxication model was established by intraperitoneal injection of aluminum maltolate for 90 days. After the exposure, the learning and memory abilities of the rats were measured by the Morris water maze behavioral test, the expression level of reactive oxygen species (ROS) in the cerebral cortex was measured by frozen sections, and the expression of PINK1, Parkin, LC3B, P62, and COXIV proteins in the hippocampal tissue was detected by Western blotting (WB).
    Results On days 3, 4, and 5 of the Morris water maze place navigation test, the escape latency of rats in each group gradually increased with the increase of the exposure dose (P<0.05). On day 6, the number of times the rats in the high-dose group crossed the platform and the platform quadrant decreased compared with the control group and the low- and medium-dose groups (P<0.05). With the increase of the exposure dose in each group, the ROS level in the cerebral cortex of rats gradually increased (P<0.05), and the content of glutathione peroxidase (GSH-Px) gradually decreased (P<0.05). The relative expression levels of PINK1, Parkin, and LC3B in the hippocampal tissue of rats in each group gradually increased with the increase of the exposure dose (P<0.05), while the relative expression levels of P62 and COXIV gradually decreased with the increase of the exposure dose (P<0.05).
    Conclusions Subchronic aluminum exposure can impair learning and memory function in rats, activate the PINK1/Parkin pathway LC3B/P62/COXIV pathway, and induce mitophagy.

     

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