Nutritional Sciences Department, Texas Tech University, Lubbock, TX, USA.
Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Hum Mol Genet. 2021 May 29;30(10):847-864. doi: 10.1093/hmg/ddab054.
The purpose of this study is to study the neuroprotective role of selective serotonin reuptake inhibitor (SSRI), citalopram, against Alzheimer's disease (AD). Multiple SSRIs, including citalopram, are reported to treat patients with depression, anxiety and AD. However, their protective cellular mechanisms have not been studied completely. In the current study, we investigated the protective role of citalopram against impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective mitophagy and synaptic dysfunction in immortalized mouse primary hippocampal cells (HT22) expressing mutant APP (SWI/IND) mutations. Using quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed mutant full-length APP/C-terminal fragments and Aβ levels and mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes in mAPP-HT22 cells and mAPP-HT22 cells treated with citalopram. Increased levels of mRNA levels of mitochondrial fission genes, decreased levels of fusion biogenesis, autophagy, mitophagy and synaptic genes were found in mAPP-HT22 cells relative to WT-HT22 cells. However, mAPP-HT22 cells treated with citalopram compared to mAPP-HT22 cells revealed reduced levels of the mitochondrial fission genes, increased fusion, biogenesis, autophagy, mitophagy and synaptic genes. Our protein data agree with mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells; these were reversed in citalopram-treated mAPP-HT22 cells. Cell survival rates were increased in citalopram-treated mAPP-HT22 relative to citalopram-untreated mAPP-HT22. Further, mAPP and C-terminal fragments werealso reduced in citalopram-treated cells. These findings suggest that citalopram reduces mutant APP and Aβ and mitochondrial toxicities and may have a protective role of mutant APP and Aβ-induced injuries in patients with depression, anxiety and AD.
这项研究的目的是研究选择性 5-羟色胺再摄取抑制剂（SSRI）西酞普兰对阿尔茨海默病（AD）的神经保护作用。包括西酞普兰在内的多种 SSRIs 被报道可用于治疗抑郁症、焦虑症和 AD 患者。然而，它们的保护细胞机制尚未被完全研究。在本研究中，我们研究了西酞普兰对表达突变 APP（SWI/IND）突变的永生化小鼠海马细胞（HT22）中线粒体动力学受损、线粒体生物发生缺陷、线粒体自噬缺陷和突触功能障碍的保护作用。我们使用定量 RT-PCR、免疫印迹、生化方法和透射电子显微镜方法评估了 mAPP-HT22 细胞和西酞普兰处理的 mAPP-HT22 细胞中突变全长 APP/C 端片段和 Aβ 水平以及线粒体动力学、生物发生、自噬和突触基因的 mRNA 和蛋白水平。与 WT-HT22 细胞相比，mAPP-HT22 细胞中线粒体分裂基因的 mRNA 水平升高，融合、生物发生、自噬、线粒体自噬和突触基因水平降低。然而，与 mAPP-HT22 细胞相比，用西酞普兰处理的 mAPP-HT22 细胞中线粒体分裂基因水平降低，融合、生物发生、自噬、线粒体自噬和突触基因水平升高。我们的蛋白质数据与 mRNA 水平一致。透射电镜显示 mAPP-HT22 细胞中线粒体数量显著增加，线粒体长度缩短；西酞普兰处理的 mAPP-HT22 细胞中这些情况得到逆转。与未用西酞普兰处理的 mAPP-HT22 细胞相比，用西酞普兰处理的 mAPP-HT22 细胞的细胞存活率增加。此外，用西酞普兰处理的细胞中的 mAPP 和 C 端片段也减少。这些发现表明西酞普兰降低了突变 APP 和 Aβ 以及线粒体毒性，并可能对抑郁症、焦虑症和 AD 患者中的突变 APP 和 Aβ 诱导损伤具有保护作用。
