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

IF 3.6 4区医学 Q3 CELL BIOLOGY

Cellular and Molecular Neurobiology Pub Date : 2025-07-07 DOI:10.1007/s10571-025-01590-w

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

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引用次数: 0

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.

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

阿尔茨海默病（AD）是痴呆症的主要原因，其特征是神经炎症和免疫失调。血管周围巨噬细胞（pvm）在AD的发生和发展中起着至关重要的作用，但具体的分子机制仍未得到充分研究。本研究利用单细胞测序结合孟德尔随机化（Mendelian randomization， MR）分析，探讨了pvm在AD中的分子机制。我们分析了GSE264648和eQTLGen的数据，确定了与AD风险显著相关的四个关键基因：IFNGR1、KLHL5、NUMB和WDFY4。功能注释显示pvm参与免疫调节和代谢途径，特别是IL-6_JAK_STAT3和Notch信号通路。免疫浸润分析显示M2巨噬细胞在AD患者中增加，提示其在神经炎症中的作用。伪时间分析强调了pvm在疾病进展过程中的发育变化。我们的研究结果为pvm在AD中的作用提供了新的见解，并为未来通过pvm靶向干预调节神经炎症和减缓AD进展的研究提供了基础。

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来源期刊

Cellular and Molecular Neurobiology 生物-神经科学

CiteScore

7.70

自引率

0.00%

发文量

137

审稿时长

4-8 weeks

期刊介绍： Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.