Xie Nanchang, Wu Chuanjie, Wang Cui, Cheng Xuan, Zhang Lu, Zhang Haifeng, Lian Yajun
Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Clinical Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Brain Res. 2017 Dec 1;1676:100-106. doi: 10.1016/j.brainres.2017.08.035. Epub 2017 Sep 20.
Amyloid-beta (Aβ) has been shown to induce microglial apoptosis, which is itself sensitive to disturbed mitochondrial calcium (Ca) homeostasis. The mitochondrial calcium uniporter (MCU) plays an important regulatory role in mitochondrial Ca homeostasis, but its role in Aβ-induced microglia apoptosis is unknown. In this study, we found increased mitochondrial Ca concentration in Aβ-treated primary microglia and BV-2 cells; also, the MCU inhibitor Ru360 significantly attenuated Aβ-induced microglial apoptosis, whereas the MCU activator spermine augmented it. In addition, Ru360 significantly attenuated Aβ-induced mitochondrial reactive oxygen species (ROS) production, as well as endoplasmic reticulum (ER) stress characterized by glucose-regulated protein 78 (GRP78) and C/-EBP homologous protein (CHOP) expression. Spermine, however, exerted the opposite effects on mitochondrial ROS production and ER stress. We also found that mitochondria-targeted antioxidant (Mito-TEMPO) treatment decreased GRP78 and CHOP expression in Aβ-treated microglia. Moreover, blocking endogenous CHOP expression using a CHOP small interfering RNA (siRNA) attenuated Aβ-induced cell death. Altogether, our data suggested that 1) inhibition of MCU exerts a neuroprotective effect on Aβ-induced microglia apoptosis, and 2) that the underlying mechanism may be related to reducing mitochondrial ROS-mediated ER stress.
β淀粉样蛋白（Aβ）已被证明可诱导小胶质细胞凋亡，而小胶质细胞凋亡本身对线粒体钙（Ca）稳态紊乱敏感。线粒体钙单向转运体（MCU）在维持线粒体钙稳态中发挥重要调节作用，但其在Aβ诱导的小胶质细胞凋亡中的作用尚不清楚。在本研究中，我们发现经Aβ处理的原代小胶质细胞和BV-2细胞中线粒体钙浓度升高；此外，MCU抑制剂Ru360显著减弱Aβ诱导的小胶质细胞凋亡，而MCU激活剂精胺则增强了这种凋亡。另外，Ru360显著减弱Aβ诱导的线粒体活性氧（ROS）生成以及以葡萄糖调节蛋白78（GRP78）和C/EBP同源蛋白（CHOP）表达为特征的内质网（ER）应激。然而，精胺对线粒体ROS生成和ER应激产生相反的作用。我们还发现，线粒体靶向抗氧化剂（Mito-TEMPO）处理可降低经Aβ处理的小胶质细胞中GRP78和CHOP的表达。此外，使用CHOP小干扰RNA（siRNA）阻断内源性CHOP表达可减弱Aβ诱导的细胞死亡。总之，我们的数据表明：1）抑制MCU对Aβ诱导的小胶质细胞凋亡具有神经保护作用；2）其潜在机制可能与减轻线粒体ROS介导的ER应激有关。
