Microglial mechanisms drive amyloid-ß clearance in immunized patients with Alzheimer's disease [dataset1]

Alzheimer's disease (AD) therapies utilizing amyloid-ß (Aß) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aß clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aß immunization in the AD brain. We compare actively immunized AD patients with nonimmunized AD patients and neurologically healthy controls, identifying distinct microglial states associated with Aß clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aß removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aß removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aß clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aß removal and shed light on the role of microglia in immune-mediated Aß clearance. Importantly, our work uncovers potential molecular targets that could enhance Aß-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD. Overall design: 25 samples: 6 Non-Neurological Diseased (NND); 6 AD Non-Immunized AD (nAD); 13 AN1792 Immunized AD (iAD) Please note that Seurat object(s) were removed on March 17, 2025, as they were uploaded prior to revisions and contained outdated cell/spot annotations. Any Seurat objects downloaded before this date should not be used. For access to updated Seurat objects, please contact [e-mail].

阿尔茨海默病（Alzheimer's Disease, AD）靶向淀粉样蛋白-β（amyloid-β, Aβ）的免疫治疗在临床试验中已展现出应用潜力。然而，免疫治疗后AD患者脑内Aβ清除的具体分子机制仍未明确。本研究借助空间转录组（spatial transcriptomics）技术，探究主动免疫与被动免疫两种Aβ免疫策略在AD脑内的作用效果。
本研究对比了接受主动免疫的AD患者、未接受免疫的AD患者以及神经健康对照人群，筛选出与Aβ清除相关的特异性小胶质细胞激活状态。结合高分辨率空间转录组与单细胞RNA测序（single-cell RNA sequencing）技术，本研究深入解析了仑卡奈单抗（lecanemab）治疗后介导Aβ清除的转录调控通路。研究发现不同脑区存在具有空间特异性的小胶质细胞应答反应。
转录组分析显示，在两种免疫策略下的小胶质细胞中，髓系细胞触发受体2（triggering receptor expressed on myeloid cells 2, TREM2）与载脂蛋白E（apolipoprotein E, APOE）均呈上调表达，且其表达水平与抗体应答及Aβ清除效率呈正相关。此外，本研究证实脑内髓系细胞的补体信号通路参与了免疫治疗后的Aβ清除过程。
上述研究结果为解析Aβ清除的转录调控机制提供了新视角，同时阐明了小胶质细胞在免疫介导Aβ清除过程中的关键作用。尤为重要的是，本研究筛选出可用于优化Aβ靶向免疫治疗的潜在分子靶点，为开发更高效的AD治疗策略提供了全新方向。
实验整体设计：共包含25例样本，其中6例为非神经疾病对照（Non-Neurological Diseased, NND）、6例为未免疫AD患者（non-immunized AD, nAD）、13例为接受AN1792免疫的AD患者（AN1792 Immunized AD, iAD）。
请注意：本数据集的Seurat对象（Seurat object）已于2025年3月17日移除，原因是该对象在修订前上传，且包含过时的细胞/斑点注释信息。2025年3月17日前下载的Seurat对象请勿继续使用。若需获取更新后的Seurat对象，请联系邮箱[e-mail].