Mrdjen Dunja, Cannon Bryan J, Amouzgar Meelad, Kim YeEun, Liu Candace, Vijayaragavan Kausalia, Camacho Christine, Spence Angie, McCaffrey Erin F, Bharadwaj Anusha, Tebaykin Dmitry, Bukhari Syed, Bosse Marc, Hartmann Felix J, Kagel Adam, Oliveria John Paul, Yakabi Koya, Serrano Geidy E, Corrada Maria M, Kawas Claudia H, Tibshirani Robert, Beach Thomas G, Corces M Ryan, Greenleaf Will, Angelo R Michael, Montine Thomas, Bendall Sean C
Department of Pathology, Stanford University, School of Medicine, Palo Alto, CA, USA.
Systems Immunology and Single-Cell Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nat Immunol. 2025 Jul 22. doi: 10.1038/s41590-025-02203-w.
Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.
小胶质细胞与衰老、神经退行性变和阿尔茨海默病（AD）有关。低通量蛋白质成像无法捕捉人类大脑中的细胞状态和相互作用，这与啮齿动物模型不同。在这里，我们使用多重离子束成像在认知正常的人类大脑中对细胞状态和生态位进行空间映射，识别出一系列蛋白质组学小胶质细胞图谱。该图谱由跨脑区倾斜并根据微环境进行分区的免疫激活状态定义，能够识别出十位认知正常个体的小胶质细胞中的蛋白质组学趋势，并与单核表观遗传分析相互验证，揭示相关分子功能。值得注意的是，AD组织在蛋白质组图谱末端的免疫活性细胞中表现出调节变化，包括CD33和CD44富集以及HLA-DR、P2RY12和载脂蛋白E表达降低。这些发现建立了一个针对AD特异性小胶质细胞状态的原位单细胞空间蛋白质组学框架。
