Unveiling the Impact of Microglial Cells in Alzheimer's Disease Pathogenesis: Insights from Single-Cell RNA-seq Analysis and In Vivo Validation

Abstract

Abstract Alzheimer's disease (AD), a prevalent global cause of dementia lacking a cure, has traditionally been studied from a molecular perspective. However, our investigation delved into the intricate cellular dimensions of AD, focusing on microglial cells, the primary immune cells in the central nervous system (CNS). Through a single-cell approach using scRNA-seq, we revealed an increased presence of microglial cells in AD samples. Utilizing this advanced technology, we unveiled the biological pathways, cellular interactions, and key genes driving AD progression. Notably, our findings emphasized the elevated activation of TNF-α signaling via NF-κB, P53, allograft rejection, coagulation, and hypoxia pathways in AD microglia. At the same time, the responsiveness to IFN-γ and IFN-α was diminished, and in alignment with scRNA-seq outcomes, gene expression analysis in a fly model indicated heightened Sima gene (HIF1A) expression in AD microglia. Furthermore, our study pinpointed significant ligand-receptor interactions in the microenvironment, notably including PTN/RPTPβ/ζ, a neurotrophic factor modulating neuroinflammation, and SEMA3A/PLXNB3. Additionally, we identified pivotal genes influencing AD pathogenesis and proposed potential treatments through drug repositioning, encompassing paclitaxel, carboplatin, cisplatin, imatinib, and fluorouracil. These findings provide insightful perspectives into AD pathophysiology at the cellular level and suggest promising avenues for further investigation and potential therapeutic interventions. More experimental validation is indispensable to corroborate these intricate molecular pathways.