Liu Yang, Peng Haoran, Liu Qi, Hao Jianying, Tang Chao, Yan Hanhui
College of Physical Education, Nanchang Institute of Technology, Nanchang, 330044, China.
Department of Neurology, People's Hospital of Henan University, Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China.
Neuromolecular Med. 2024 Dec 19;27(1):1. doi: 10.1007/s12017-024-08821-1.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. The neuropathology of AD appears in the hippocampus. The purpose of this work was to reveal key differentially expressed genes (DEGs) in the hippocampus of AD patients and healthy individuals. Furthermore, we established an in vivo AD-like model to validate and explore the effects of exercise on these risky genes. The datasets GSE36980 and GSE48350 were downloaded from the GEO database and visualized using R packages to obtain DEGs. Subsequently, the potential biological functions of these DEGs were predicted, PPI network interactions were screened for core genes, and Pearson correlation analysis was performed. Additionally, we determined the diagnostic value of core DEGs using ROC curves. Single-cell analysis was used to verify the cell type specificity of hub genes. Finally, we used RT-qPCR, immunohistochemistry, and immunofluorescence to validate the expression of core DEGs in model mice and to explore the beneficial mechanisms of exercise. A total of 13 differentially expressed genes (DEGs) associated with the development of AD were identified, comprising 11 down-regulated genes and 2 up-regulated genes. PPI network visualization acquired four down-regulated core DEGs with good diagnostic value. The findings from the in vivo study indicated that the mRNA expression of GABRA1, GABRG2, and SVOP decreased, and the astrocyte marker GFAP notably increased in AD mice. Surprisingly, exercise increased hippocampal GABRA1 and GABRG2 expression and decreased GFAP-positive intensity of GABRG1 localization, reducing expression of inflammatory markers TNF-α and IL-1β. In addition, exercise improved the spatial exploration ability but had little effect on the preference index in AD mice. Our data highlighted the mechanism by which exercise improves memory performance in AD patients by reducing astrocyte neurotoxicity inducing decreased hippocampal GABA receptor expression.
阿尔茨海默病（AD）是最常见的神经退行性疾病。AD的神经病理学出现在海马体中。本研究的目的是揭示AD患者和健康个体海马体中关键的差异表达基因（DEGs）。此外，我们建立了一种体内AD样模型，以验证和探索运动对这些风险基因的影响。从GEO数据库下载数据集GSE36980和GSE48350，并使用R包进行可视化以获得DEGs。随后，预测这些DEGs的潜在生物学功能，筛选PPI网络相互作用中的核心基因，并进行Pearson相关性分析。此外，我们使用ROC曲线确定核心DEGs的诊断价值。单细胞分析用于验证枢纽基因的细胞类型特异性。最后，我们使用RT-qPCR、免疫组织化学和免疫荧光来验证模型小鼠中核心DEGs的表达，并探索运动的有益机制。共鉴定出13个与AD发展相关的差异表达基因（DEGs），包括11个下调基因和2个上调基因。PPI网络可视化获得了4个具有良好诊断价值的下调核心DEGs。体内研究结果表明，AD小鼠中GABRA1、GABRG2和SVOP的mRNA表达降低，星形胶质细胞标志物GFAP显著增加。令人惊讶的是，运动增加了海马体中GABRA1和GABRG2的表达，并降低了GABRG1定位处GFAP的阳性强度，减少了炎症标志物TNF-α和IL-1β的表达。此外，运动改善了AD小鼠的空间探索能力，但对偏好指数影响不大。我们的数据突出了运动通过降低星形胶质细胞神经毒性诱导海马体GABA受体表达降低来改善AD患者记忆表现的机制。
