HIF-1α-induced microglia-mediated neuroinflammation is involved in Alzheimer's disease: Evidence from single-cell transcriptomic analysis

作者：Manyu Dong, Yilun Qian, Yao Geng, Ruiyu Wang, Yu Wang, Jili Cai, Xihui Wang, Ying Huang, Yan Liu, Wentao Liu, Qi Wu, Ying Shen · 发表于：Journal of Alzheimer s Disease · 年份：2025 · DOI：10.1177/13872877251378007 · 被引用次数：7 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer、Neurological Disease Mechanisms and Treatments

BackgroundMicroglia are central mediators of neuroinflammation in Alzheimer's disease (AD), contributing significantly to disease pathogenesis. Understanding microglial heterogeneity and their regulatory mechanisms is critical for identifying potential therapeutic targets.ObjectiveThis study aimed to investigate the diversity of microglial subpopulations in AD and uncover key transcriptional regulators driving their pathogenic activity.MethodsWe integrated bulk RNA sequencing data from AD patients and 5×FAD mouse models with single-cell RNA sequencing (scRNA-seq) to profile microglial heterogeneity. Differential gene expression, pathway enrichment, pseudotime trajectory, and SCENIC analyses were used to identify functionally distinct subsets and regulatory networks. Experimental validation was conducted through in vivo assays in 5×FAD mice and in vitro inhibition studies targeting HIF-1α.ResultsA unique microglial subpopulation, termed microglia_2, was identified with an inflammatory-angiogenic transcriptional signature that was enriched during AD progression. This subset showed significant activation of inflammatory pathways. Pseudotime and SCENIC analyses revealed HIF-1α as a master regulator of microglia_2. In 5×FAD mice, cognitive decline was accompanied by increased expression of HIF-1α and Apoe, as well as microglial activation in the prefrontal cortex. In vitro inhibition of HIF-1α significantly reduced microglial inflammation.ConclusionsOur study demonstrates that a s...