阿尔茨海默病小鼠模型中具有不同染色质可及性的空间定义小胶质细胞状态的反应，这一成果由弗莱堡大学Marco Prinz团队经过不懈努力而取得。2025年7月14日出版的《自然—神经科学》杂志发表了这一最新研究成果。

本研究结合多色荧光细胞命运图谱、单细胞转录分析、表观遗传谱、免疫组织化学和计算模型，全面表征斑块相关小胶质细胞（PAM）和非斑块相关小胶质细胞（non-PAM）在AD单主题模型中的关系。研究团队发现非PAM是一种独特的、高度动态的小胶质细胞状态，在雌性小鼠a β斑块沉积后过渡到PAM。非PAM在淀粉样蛋白沉积时调节细胞群的扩张，并对环境线索做出快速反应。事实上，Csf1信号在疾病进展过程中调节非PAM到PAM的转变。他们的数据表明，小胶质细胞状态及其相互之间的动态可能对疾病有不同的贡献，它们可能是治疗阿尔茨海默病的目标。

据悉，在阿尔茨海默病（AD）的潜在细胞导向治疗中，小胶质细胞的空间异质性仍然是一个关键但尚未完全回答的问题。淀粉样蛋白- β (Aβ)斑块附近或远离斑块的不同小胶质细胞状态的动力学及其对神经退行性疾病的影响尚不清楚。

附：英文原文

Title: Response of spatially defined microglia states with distinct chromatin accessibility in a mouse model of Alzheimer’s disease

Author: Ardura-Fabregat, Alberto, Bosch, Lance Fredrick Pahutan, Wogram, Emile, Mossad, Omar, Sankowski, Roman, Aktories, Philipp, Kieger, Lina, Cook, James, Hasavci, Dilara, Ulupinar, Hatice, Brock, Daniel, Wang, Fang, Iovino, Nicola, Wald, Samuel, Preissl, Sebastian, Yilmaz, Bahtiyar, Schnepf, Daniel, Macpherson, Andrew J., Blank, Thomas, Kierdorf, Katrin, Prinz, Marco

Issue&Volume: 2025-07-14

Abstract: Microglial spatial heterogeneity remains a crucial yet not fully answered question in the context of potential cell-directed therapies for Alzheimer’s disease (AD). There is an unclear understanding of the dynamics of distinct microglia states adjacent to or far from amyloid-beta (Aβ) plaques and their contributions to neurodegenerative diseases. Here we combine multicolor fluorescence cell fate mapping, single-cell transcriptional analysis, epigenetic profiling, immunohistochemistry and computational modeling to comprehensively characterize the relation of plaque-associated microglia (PAM) and non-plaque-associated microglia (non-PAM) in a mouse model of AD. We show that non-PAM are a distinct and highly dynamic microglial state, transitioning to PAM after Aβ plaque deposition in female mice. Non-PAM modulate the cell population expansion in response to amyloid deposition and rapidly respond to environmental cues. Indeed, Csf1 signaling modulates non-PAM-to-PAM transition during disease progression. Our data suggest that microglia states and their dynamics between each other can have distinct contributions to disease, and they may be targeted for the treatment of AD.

DOI: 10.1038/s41593-025-02006-0

Source: https://www.nature.com/articles/s41593-025-02006-0