斯坦福大学Sean C. Bendall小组的一项最新研究提出了阿尔茨海默病特异性人类小胶质细胞状态的空间蛋白质组学。该项研究成果发表在2025年7月22日出版的《自然—免疫学》上。

在这里，该研究团队以多路离子束成像为主题，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，识别蛋白质组学小胶质谱。该光谱由免疫激活状态定义，该激活状态在大脑区域中倾斜，并根据微环境进行区隔，该光谱能够识别十个认知正常个体的小胶质细胞中的蛋白质组学趋势，并与单核表观遗传学分析正交，揭示相关的分子功能。值得注意的是，AD组织在蛋白质组学谱末端的免疫活性细胞中表现出调节性变化，包括CD33和CD44的富集以及HLA-DR、P2RY12和ApoE表达的降低。这些发现建立了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。

据介绍，小胶质细胞与衰老、神经变性和阿尔茨海默病（AD）有关。与啮齿类动物模型不同，低复合蛋白成像不能捕捉人类大脑中的细胞状态和相互作用。

附：英文原文

Title: Spatial proteomics of Alzheimer’s disease-specific human microglial states

Author: 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.

Issue&Volume: 2025-07-22

Abstract: 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.

DOI: 10.1038/s41590-025-02203-w

Source: https://www.nature.com/articles/s41590-025-02203-w