传染病科Katherine Y. King小组取得一项新突破。他们揭示了TET2突变骨髓细胞通过中枢神经系统浸润和增强吞噬作用减轻小鼠阿尔茨海默病。2025年7月2日，国际知名学术期刊《细胞—干细胞》发表了这一成果。

在英国生物库中，研究团队发现TET2突变的CH与晚发性AD （LOAD）风险降低47%相关，而其他CH驱动因素则不具有保护作用。在AD的单主题模型中，TET2突变骨髓移植减少了认知能力下降和β-淀粉样斑块的形成，而DNMT3A突变骨髓没有观察到这种作用。骨髓来源的小胶质样细胞在TET2突变的骨髓受体中检测到的比例增加，TET2突变的人诱导多能干细胞（iPSC）来源的小胶质细胞比DNMT3A突变或野生型小胶质细胞更具吞噬性和高炎症性。引人注目的是，单细胞RNA测序（scRNA-seq）显示，TET2突变骨髓移植小鼠的大脑中巨噬细胞和巡逻单核细胞增加，以响应趋化因子信号。这些研究揭示了CH对外周髓细胞浸润介导的AD发病机制具有TET2特异性保护作用。

据悉，克隆造血（CH）与许多年龄相关疾病有关，但其与阿尔茨海默病（AD）的相互作用尚不清楚。

附：英文原文

Title: TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice

Author: Katie A. Matatall, Trisha K. Wathan, Minh Nguyen, Hu Chen, Alexandra McDonald, Guantong Qi, Julia A. Belk, Marcus A. Florez, Duy T. Le, Temitope Olarinde, Caitlyn Vlasschaert, Marco M. Buttigieg, Chih-wei Fan, Saul Carcamo, Ruoqiong Cao, Daniel E. Kennedy, Arushana A. Maknojia, Apoorva Thatavarty, Josaura V. Fernandez Sanchez, Hind Bouzid, Surabi Veeraragavan, Susan Crocker, Margaret A. Goodell, Antony Rodriguez, Siddhartha Jaiswal, Michael J. Rauh, Eirini P. Papapetrou, Samuele G. Marro, Katherine Y. King

Issue&Volume: 2025-07-02

Abstract: Clonal hematopoiesis (CH) is associated with many age-related diseases, but its interaction with Alzheimer’s disease (AD) remains unclear. Here, we show that TET2-mutant CH is associated with a 47% reduced risk of late-onset AD (LOAD) in the UK Biobank, whereas other drivers of CH do not confer protection. In a mouse model of AD, transplantation of Tet2-mutant bone marrow reduced cognitive decline and β-amyloid plaque formation, effects not observed with Dnmt3a-mutant marrow. Bone-marrow-derived microglia-like cells were detected at an increased rate in Tet2-mutant marrow recipients, and TET2-mutant human induced pluripotent stem cell (iPSC)-derived microglia were more phagocytic and hyperinflammatory than DNMT3A-mutant or wild-type microglia. Strikingly, single-cell RNA sequencing (scRNA-seq) revealed that macrophages and patrolling monocytes were increased in brains of mice transplanted with Tet2-mutant marrow in response to chemokine signaling. These studies reveal a TET2-specific protective effect of CH on AD pathogenesis mediated by peripheral myeloid cell infiltration.

DOI: 10.1016/j.stem.2025.06.006

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00228-0