Differential Expression of GABA Receptor-Related Genes in Alzheimer's Disease and the Positive Regulatory Role of Aerobic Exercise-From Genetic Screening to D-gal-induced AD-like Pathology Model

Abstract

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.

Keywords: Alzheimer’s disease; Astrocytes toxicity; Diagnostic marker; Differentially expressed genes; Exercise; GABA-receptor.