Niu Rui-Ze, Feng Wan-Qing, Chen Li, Bao Tian-Hao
Mental Health Center, Kunming Medical University, No. 733, Chuanjin Road, Panlong District, Kunming 650034, China.
Laboratory Zoology Department, Kunming Medical University, Kunming 650034, China.
Int J Mol Sci. 2025 May 19;26(10):4841. doi: 10.3390/ijms26104841.
Previous studies have largely overlooked cellular differential alterations across differentially affected brain regions in both disease mechanisms and therapeutic development of Alzheimer's disease (AD). This study aimed to compare the differential cellular and transcriptional changes in the prefrontal cortex (PFC) and entorhinal cortex (EC) of AD patients through an integrated single-cell transcriptomic analysis. We integrated three single-cell RNA sequencing (scRNA-seq) datasets comprising PFC and EC samples from AD patients and age-matched healthy controls. A total of 124,658 nuclei and 31 cell clusters were obtained and classified into eight major cell types, with EC exhibiting much more pronounced transcriptional alterations than PFC. Through network analysis, we pinpointed hub regulatory genes that form interconnected networks driving AD pathogenesis, findings validated by RT-qPCR showing more pronounced expression changes in EC versus PFC of AD mice. Moreover, dysregulation of the LINC01099-associated regulatory networks in the PFC and EC, showing correlation with AD progression, may present new therapeutic targets for AD. Together, these results suggest that effective AD biomarkers and therapeutic strategies may require simultaneous, precise targeting of specific cell populations across multiple brain regions.
先前的研究在很大程度上忽视了在阿尔茨海默病（AD）的疾病机制和治疗开发中，不同受影响脑区之间的细胞差异变化。本研究旨在通过综合单细胞转录组分析，比较AD患者前额叶皮质（PFC）和内嗅皮质（EC）中细胞和转录的差异变化。我们整合了三个单细胞RNA测序（scRNA-seq）数据集，这些数据集包含来自AD患者和年龄匹配的健康对照的PFC和EC样本。共获得124,658个细胞核和31个细胞簇，并将其分为八种主要细胞类型，其中EC表现出比PFC更明显的转录变化。通过网络分析，我们确定了形成驱动AD发病机制的相互连接网络的枢纽调控基因，RT-qPCR验证的结果显示，与AD小鼠的PFC相比，EC中的表达变化更为明显。此外，PFC和EC中LINC01099相关调控网络的失调与AD进展相关，这可能为AD提供新的治疗靶点。总之，这些结果表明，有效的AD生物标志物和治疗策略可能需要同时、精确地针对多个脑区的特定细胞群。
