Comprehensive and In-Depth Molecular and Pathway Studies of the Hippocampus in Alzheimer’S Disease Publisher Pubmed



Pour FT ; Saadatpour F ; Salari A
Source: Cellular and Molecular Neurobiology Published:2025

Abstract

Alzheimer’s disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein–protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus—a subregion selectively affected in early AD—we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, “7-alpha-hydroxycholesterol” was upregulated, while “vacuolar organization” was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three—MRPS7, RPL5, and GFM1—along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the “inflammatory response”, “7-alpha-hydroxycholesterol”, “Mitochondrial dysfunction” and “Oxidative phosphorylation” pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer’s disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research. © The Author(s) 2025.