Yang Hongkuan, Guan Hongpeng, Yang Mingchun, Liu Ziyi, Takeuchi Shigeko, Yanagisawa Daijiro, Vincent Steven R, Zhao Shiguang, Tooyama Ikuo
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan Department of Neurosurgery, 1st Affiliated Hospital, Harbin Medical University, Harbin, China.
Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Japan.
J Alzheimers Dis. 2015;45(3):797-811. doi: 10.3233/JAD-142595.
Studies have shown an increased expression of mitochondrial ferritin (FtMt) and an antioxidant role for the protein in the brains of Alzheimer's disease (AD) patients. However, little information is available concerning the role of FtMt in other AD pathologies, including inflammation and amyloidogenesis. Therefore, we investigated the regulation and function of FtMt in inflammation and amyloidogenesis. FtMt protein expression was increased by proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6), whereas FtMt mRNA levels were increased by TNF-α but not by IL-1β or IL-6 in IMR-32 cells. The transcription factor nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082, suppressed this TNF-α-induced FtMt expression. FtMt overexpression increased NF-κB activity and translocation of p65 into the nucleus in HEK293 cells. Conversely, knockdown of FtMt attenuated TNF-α-induced NF-κB activity. Overexpression of FtMt inhibited TNF-α-induced apoptosis in the cell culture. FtMt overexpression reduced iron-mediated expression of amyloid-β protein precursor and decreased NF-κB-dependent increases in β- and γ-secretase, leading to decreased amyloid-β production. Our data provide new insights into the mechanism underlying the regulation of FtMt expression by proinflammatory cytokines and indicate further roles for FtMt in AD.
研究表明，线粒体铁蛋白（FtMt）在阿尔茨海默病（AD）患者大脑中的表达增加，且该蛋白具有抗氧化作用。然而，关于FtMt在其他AD病理过程中的作用，包括炎症和淀粉样蛋白生成，目前所知甚少。因此，我们研究了FtMt在炎症和淀粉样蛋白生成中的调控及功能。在IMR-32细胞中，促炎细胞因子，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素6（IL-6），可增加FtMt蛋白表达，而TNF-α可增加FtMt mRNA水平，IL-1β和IL-6则无此作用。转录因子核因子-κB（NF-κB）抑制剂Bay 11-7082可抑制TNF-α诱导的FtMt表达。在HEK293细胞中，FtMt过表达可增加NF-κB活性及p65向细胞核的转位。相反，敲低FtMt可减弱TNF-α诱导的NF-κB活性。FtMt过表达可抑制细胞培养中TNF-α诱导的细胞凋亡。FtMt过表达可降低铁介导的淀粉样β蛋白前体的表达，并减少NF-κB依赖性的β和γ分泌酶增加，从而导致淀粉样β生成减少。我们的数据为促炎细胞因子调控FtMt表达的机制提供了新见解，并表明FtMt在AD中具有进一步的作用。
