Song Jia-Yi, Jia Yong, Han Hao, Yang Xue-Han, Zhang Jing, Zhang Qiang, Wang Su-Shan, Wang Chun-Yan, Chen Li, Zhang Ming
Department of Pharmacology, Basic College of Medicine, Jilin University, Changchun, Jilin Province, China; Department of General Practice, The First Hospital of Jilin University, Changchun, Jilin Province, China.
School of nursing, Jilin University, Changchun, Jilin Province, China.
Mitochondrion. 2024 Sep;78:101918. doi: 10.1016/j.mito.2024.101918. Epub 2024 Jun 12.
Alzheimer's disease (AD) is currently one of the most serious public health concerns in the world. However, the best approach to treat AD has yet to be discovered, implying that we must continue to work hard to find new AD target genes. In this study, we further analysed Gene Expression Omnibus (GEO) data and discovered that the expression of the Mitochondria glutamate carrier SLC25A18 is associated with AD by screening the differentially expressed genes in different regions of the brains of Alzheimer's disease patients. To verify the expression of SLC25A18 during Alzheimer's disease development, we analysed animal models (5×FAD transgenic AD animal model, chemically induced AD animal model, natural ageing animal model), and the results showed that the expression of SLC25A18 was increased in animal models of AD. Further investigation of the different regions found that SLC25A18 expression was elevated in the EC, TeA, and CA3, and expressed in neurons. Next, We found that Aβ42 treatment elevated SLC25A18 expression in Neuro 2A cells. Reducing SLC25A18 expression attenuated mitochondrial dysfunction and neuronal apoptosis caused by Aβ42. Overexpression of SLC25A18 increased ATP and intracellular superoxide anions but decreased mitochondrial membrane potential. The results indicate that SLC25A18 affects mitochondrial function and neuronal apoptosis, and is related to AD, which makes it a potential target for treating brain dysfunction.
阿尔茨海默病（AD）是目前全球最严重的公共卫生问题之一。然而，治疗AD的最佳方法尚未找到，这意味着我们必须继续努力寻找新的AD靶基因。在本研究中，我们进一步分析了基因表达综合数据库（GEO）数据，通过筛选阿尔茨海默病患者大脑不同区域的差异表达基因，发现线粒体谷氨酸载体SLC25A18的表达与AD相关。为了验证SLC25A18在阿尔茨海默病发展过程中的表达情况，我们分析了动物模型（5×FAD转基因AD动物模型、化学诱导AD动物模型、自然衰老动物模型），结果显示在AD动物模型中SLC25A18的表达增加。对不同区域的进一步研究发现，SLC25A18在嗅内皮质（EC）、颞叶杏仁核（TeA）和海马CA3区表达升高，且在神经元中表达。接下来，我们发现Aβ42处理可提高Neuro 2A细胞中SLC25A18的表达。降低SLC25A18的表达可减轻Aβ42引起的线粒体功能障碍和神经元凋亡。过表达SLC25A18可增加ATP和细胞内超氧阴离子，但降低线粒体膜电位。结果表明，SLC25A18影响线粒体功能和神经元凋亡，与AD相关，这使其成为治疗脑功能障碍的潜在靶点。
