Matatall Katie A, Wathan Trisha K, Nguyen Minh, Chen Hu, McDonald Alexandra, Qi Guantong, Belk Julia A, Florez Marcus A, Le Duy T, Olarinde Temitope, Vlasschaert Caitlyn, Buttigieg Marco M, Fan Chih-Wei, Carcamo Saul, Cao Ruoqiong, Kennedy Daniel E, Maknojia Arushana A, Thatavarty Apoorva, Fernandez Sanchez Josaura V, Bouzid Hind, Veeraragavan Surabi, Crocker Susan, Goodell Margaret A, Rodriguez Antony, Jaiswal Siddhartha, Rauh Michael J, Papapetrou Eirini P, Marro Samuele G, King Katherine Y
Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Stem Cell. 2025 Jun 24. doi: 10.1016/j.stem.2025.06.006.
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.
克隆性造血（CH）与许多年龄相关疾病有关，但其与阿尔茨海默病（AD）的相互作用仍不清楚。在此，我们表明，在英国生物银行中，TET2突变的CH与晚发性AD（LOAD）风险降低47%相关，而CH的其他驱动因素则不具有保护作用。在AD小鼠模型中，移植Tet2突变的骨髓可减少认知衰退和β-淀粉样斑块形成，而Dnmt3a突变的骨髓则未观察到这些效果。在Tet2突变的骨髓受体中，骨髓来源的小胶质细胞样细胞的检测率增加，并且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作用和炎症反应。引人注目的是，单细胞RNA测序（scRNA-seq）显示，移植Tet2突变骨髓的小鼠大脑中，巨噬细胞和巡逻单核细胞因趋化因子信号而增加。这些研究揭示了CH对由外周髓样细胞浸润介导的AD发病机制具有TET2特异性保护作用。
