Chen Xin, Jiang Xue-Mei, Zhao Lin-Jing, Sun Lin-Lin, Yan Mei-Ling, Tian You, Zhang Shuai, Duan Ming-Jing, Zhao Hong-Mei, Li Wen-Rui, Hao Yang-Yang, Wang Li-Bo, Xiong Qiao-Jie, Ai Jing
Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, College of Pharmacy of Harbin Medical University, Harbin 150086, China.
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Cell Death Dis. 2017 Jun 1;8(6):e2850. doi: 10.1038/cddis.2017.243.
Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer's disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and cortices. It also led to increase in N-terminal β-amyloid precursor protein (N-APP) and death receptor-6 (DR6) protein levels and in the activation of caspase-3 and caspase-6. Further study showed that DR6 protein was downregulated by miR-195 overexpression, upregulated by miR-195 inhibition, and unchanged by binding-site mutation and miR-masks. Knockdown of endogenous miR-195 by lentiviral vector-mediated overexpression of its antisense molecule (lenti-pre-AMO-miR-195) decreased the total length, numbers and crossings of dendrites and neuron death, upregulated N-APP and DR6 levels, and elevated cleaved caspase-3 and caspase-6 levels. Overexpression of miR-195 using lenti-pre-miR-195 prevented these changes triggered by 2VO. We conclude that miR-195 is involved in CBH-induced dendritic degeneration and neuron death through activation of the N-APP/DR6/caspase pathway.
突触可塑性受损和神经元丢失是阿尔茨海默病和血管性痴呆的标志。在此，我们发现双侧颈总动脉闭塞（2VO）导致的慢性脑灌注不足（CBH）减少了大鼠海马体和皮质中树突的总长度、数量和分支，并导致神经元死亡。它还导致N端β淀粉样前体蛋白（N-APP）和死亡受体-6（DR6）蛋白水平升高，以及半胱天冬酶-3和半胱天冬酶-6的激活。进一步研究表明，miR-195过表达可下调DR6蛋白，miR-195抑制可上调DR6蛋白，而结合位点突变和miR-掩码对其无影响。慢病毒载体介导的反义分子（lenti-pre-AMO-miR-195）过表达内源性miR-195可降低树突的总长度、数量和分支以及神经元死亡，上调N-APP和DR6水平，并提高裂解的半胱天冬酶-3和半胱天冬酶-6水平。使用lenti-pre-miR-195过表达miR-195可预防2VO引发的这些变化。我们得出结论，miR-195通过激活N-APP/DR6/半胱天冬酶途径参与CBH诱导的树突退化和神经元死亡。
