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, Katherine Y. King
{"title":"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的进展","authors":"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, Katherine Y. King","doi":"10.1016/j.stem.2025.06.006","DOIUrl":null,"url":null,"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.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"3 1","pages":""},"PeriodicalIF":19.8000,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice\",\"authors\":\"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, Katherine Y. King\",\"doi\":\"10.1016/j.stem.2025.06.006\",\"DOIUrl\":null,\"url\":null,\"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.\",\"PeriodicalId\":9665,\"journal\":{\"name\":\"Cell stem cell\",\"volume\":\"3 1\",\"pages\":\"\"},\"PeriodicalIF\":19.8000,\"publicationDate\":\"2025-07-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell stem cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.stem.2025.06.006\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.stem.2025.06.006","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice
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.
期刊介绍:
Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.