Nutritional Sciences Department, Texas Tech University, Lubbock, TX 79409-1270, USA.
Internal Medicine Department, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Hum Mol Genet. 2021 May 28;30(9):789-810. doi: 10.1093/hmg/ddab091.
In the current study, we investigated the protective role of citalopram against cognitive decline, impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective autophagy, mitophagy and synaptic dysfunction in APP transgenic mouse model of Alzheimer's disease (ad). We treated 12-month-old wild-type (WT) and age-matched transgenic APP mice with citalopram for 2 months. Using Morris Water Maze and rotarod tests, quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed cognitive behavior, RNA and protein levels of mitochondrial dynamics, biogenesis, autophagy, mitophagy, synaptic, ad-related and neurogenesis genes in wild-type and APP mice treated and untreated with citalopram. Citalopram-treated APP mice relative to citalopram-untreated APP mice exhibited improved cognitive behavior. Increased levels of mRNA associated with mitochondrial fission and ad-related genes; decreased levels of fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes were found in APP mice relative to WT mice. However, APP mice treated with citalopram compared to citalopram-untreated APP mice revealed reduced levels of the mitochondrial fission and ad-related genes and increased fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes. Our protein data agree with the mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice; these were reversed in citalopram-treated APP mice. Further, Golgi-cox staining analysis revealed reduced dendritic spines in APP mice relative to WT mice. However, citalopram-treated APP mice showed significantly increased dendritic spines, indicating that citalopram enhances spine density, synaptic activity and improved cognitive function in APP mice. These findings suggest that citalopram reduces cognitive decline, Aβ levels and mitochondrial and synaptic toxicities and may have a strong protective role against mutant APP and Aβ-induced injuries in patients with depression, anxiety and ad.
在当前的研究中，我们研究了西酞普兰对阿尔茨海默病（ad）APP 转基因小鼠模型认知能力下降、线粒体动力学受损、线粒体生物发生缺陷、自噬缺陷、噬线粒体和突触功能障碍的保护作用。我们用西酞普兰治疗了 12 个月大的野生型（WT）和年龄匹配的转基因 APP 小鼠 2 个月。使用 Morris 水迷宫和旋转棒测试、定量 RT-PCR、免疫印迹、生化方法和透射电子显微镜方法，我们评估了野生型和未经西酞普兰处理和处理的 APP 小鼠的认知行为、线粒体动力学、生物发生、自噬、噬线粒体、突触、ad 相关和神经发生基因的 RNA 和蛋白质水平。与未经西酞普兰处理的 APP 小鼠相比，西酞普兰处理的 APP 小鼠表现出改善的认知行为。与 WT 小鼠相比，APP 小鼠中线粒体分裂和 ad 相关基因的 mRNA 水平增加；融合、生物发生、自噬、噬线粒体、突触和神经发生基因的水平降低。然而，与未经西酞普兰处理的 APP 小鼠相比，用西酞普兰处理的 APP 小鼠显示出较低的线粒体分裂和 ad 相关基因水平，以及较高的融合、生物发生、自噬、噬线粒体、突触和神经发生基因水平。我们的蛋白质数据与 mRNA 水平一致。透射电子显微镜显示 APP 小鼠中线粒体数量显著增加，线粒体长度减少；这些在西酞普兰处理的 APP 小鼠中得到逆转。此外，高尔基-考克斯染色分析显示，APP 小鼠的树突棘比 WT 小鼠减少。然而，西酞普兰处理的 APP 小鼠显示出明显增加的树突棘，表明西酞普兰增强了 APP 小鼠的棘密度、突触活性和认知功能。这些发现表明，西酞普兰可减少认知能力下降、Aβ 水平以及线粒体和突触毒性，并可能对抑郁、焦虑和 ad 患者中的突变 APP 和 Aβ 诱导损伤具有强大的保护作用。
