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
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.
Nat Neurosci. 2025 Jul 14. doi: 10.1038/s41593-025-02006-0.
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.
在针对阿尔茨海默病（AD）的潜在细胞定向治疗背景下，小胶质细胞的空间异质性仍然是一个关键但尚未完全解答的问题。对于与淀粉样β（Aβ）斑块相邻或远离的不同小胶质细胞状态的动态变化及其对神经退行性疾病的贡献，目前尚不清楚。在此，我们结合多色荧光细胞命运图谱、单细胞转录分析、表观遗传谱分析、免疫组织化学和计算模型，以全面表征AD小鼠模型中斑块相关小胶质细胞（PAM）和非斑块相关小胶质细胞（非PAM）的关系。我们发现，非PAM是一种独特且高度动态的小胶质细胞状态，在雌性小鼠中，Aβ斑块沉积后会转变为PAM。非PAM会响应淀粉样蛋白沉积调节细胞群体扩张，并对环境线索迅速做出反应。事实上，Csf1信号在疾病进展过程中调节非PAM向PAM的转变。我们的数据表明，小胶质细胞状态及其相互之间的动态变化可能对疾病有不同的贡献，并且它们可能成为AD治疗的靶点。
