比利时法兰德斯生物技术研究所Bart De Strooper小组在研究中取得进展。他们发现异种移植的人类小胶质细胞在阿尔茨海默病相关淀粉样蛋白-β病理反应中，表现出不同的转录组状态。2024年3月27日，国际知名学术期刊《自然—神经科学》发表了这一成果。

课题组生成了138,577个人类干细胞来源的小胶质细胞异种移植，在野生型对照和淀粉样蛋白病理App^NL-G-F模型大脑中的单细胞表达谱。异种移植的人类小胶质细胞具有与疾病相关的特征，与单核小胶质细胞相似，但表现出更明显的人类白细胞抗原或HLA状态，可能与淀粉样斑块反应中的抗原呈递有关。

人类小胶质细胞反应还包括促炎细胞因子/趋化因子细胞因子反应，小胶质细胞或CRM对低聚物Aβ低聚物的反应。移植小胶质细胞中TREM2或APOE的基因缺失，以及APOE多态性和TREM2^R47H的表达对这些反应有不同的调节作用。其他阿尔茨海默病风险基因的表达，在淀粉样蛋白病理引起的不同细胞状态中受到差异调节。因此，研究团队已经确定了人类小胶质细胞，在对阿尔茨海默病相关病理的多管齐下反应中，采用的多种转录组细胞状态，这应该在转化研究中加以考虑。

据介绍，小胶质细胞是阿尔茨海默病病理的核心角色，但由于遗传多样性、死后延迟和病理混合，分析人脑样本中的小胶质细胞状态具有挑战性。

附：英文原文

Title: Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related amyloid-β pathology

Author: Mancuso, Renzo, Fattorelli, Nicola, Martinez-Muriana, Anna, Davis, Emma, Wolfs, Leen, Van Den Daele, Johanna, Geric, Ivana, Premereur, Jessie, Polanco, Paula, Bijnens, Baukje, Preman, Pranav, Serneels, Lutgarde, Poovathingal, Suresh, Balusu, Sriram, Verfaillie, Catherine, Fiers, Mark, De Strooper, Bart

Issue&Volume: 2024-03-27

Abstract: Microglia are central players in Alzheimer’s disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aβ oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer’s disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer’s disease-related pathology, which should be taken into account in translational studies.

DOI: 10.1038/s41593-024-01600-y

Source: https://www.nature.com/articles/s41593-024-01600-y