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阿尔茨海默病中血管周围巨噬细胞的分子机制：来自单细胞测序和孟德尔随机化的见解

Molecular Mechanisms of Perivascular Macrophages in Alzheimer's Disease: Insights from Single-Cell Sequencing and Mendelian Randomization.

作者信息

Zhang Min, Liu Shufang, Zhao Yanan, Wu Ping, Tian Shouyuan, Wu Zhifang, Li Sijin

机构信息

Department of Nuclear Medicine, The First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, Shanxi, China.

Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, Shanxi, China.

出版信息

Cell Mol Neurobiol. 2025 Jul 7;45(1):65. doi: 10.1007/s10571-025-01590-w.

DOI:10.1007/s10571-025-01590-w
PMID:40622473
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12234932/
Abstract

Alzheimer's disease (AD) is a leading cause of dementia characterized by neuroinflammation and immune dysregulation. Perivascular macrophages (PVMs) play a crucial role in the onset and progression of AD, yet the specific molecular mechanisms remain understudied. This study explored the molecular mechanisms of PVMs in AD using single-cell sequencing combined with Mendelian randomization (MR) analysis. We analyzed data from GSE264648 and eQTLGen and identified four key genes that were significantly associated with AD risk: IFNGR1, KLHL5, NUMB, and WDFY4. Functional annotation revealed that PVMs were involved in immune regulation and metabolic pathways, particularly IL-6_JAK_STAT3 and Notch signaling. Immune infiltration analysis showed increased M2 macrophages in AD patients, suggesting their roles in neuroinflammation. Pseudo-time analysis highlighted developmental shifts in PVMs during disease progression. Our findings offer novel insights into the role of PVMs in AD and provide a foundation for future research on modulating neuroinflammation and slowing AD progression through PVM-targeted interventions.

摘要

阿尔茨海默病（AD）是痴呆症的主要病因，其特征为神经炎症和免疫失调。血管周围巨噬细胞（PVMs）在AD的发病和进展中起关键作用，但其具体分子机制仍研究不足。本研究采用单细胞测序结合孟德尔随机化（MR）分析，探索PVMs在AD中的分子机制。我们分析了来自GSE264648和eQTLGen的数据，鉴定出四个与AD风险显著相关的关键基因：IFNGR1、KLHL5、NUMB和WDFY4。功能注释显示，PVMs参与免疫调节和代谢途径，特别是IL-6_JAK_STAT3和Notch信号通路。免疫浸润分析表明，AD患者中M2巨噬细胞增加，提示其在神经炎症中的作用。伪时间分析突出了疾病进展过程中PVMs的发育变化。我们的研究结果为PVMs在AD中的作用提供了新见解，并为未来通过靶向PVMs干预来调节神经炎症和减缓AD进展的研究奠定了基础。

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