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

Katie A Matatall¹, Trisha K Wathan², Minh Nguyen³, Hu Chen⁴, Alexandra McDonald⁵, Guantong Qi⁶, Julia A Belk⁷, Marcus A Florez⁸, Duy T Le⁹, Temitope Olarinde¹⁰, Caitlyn Vlasschaert⁵, Marco M Buttigieg¹¹, Chih-Wei Fan³, Saul Carcamo³, Ruoqiong Cao¹, Daniel E Kennedy 2nd¹, Arushana A Maknojia¹, Apoorva Thatavarty¹, Josaura V Fernandez Sanchez¹², Hind Bouzid⁷, Surabi Veeraragavan¹³, Susan Crocker¹⁴, Margaret A Goodell¹⁵, Antony Rodriguez¹⁶, Siddhartha Jaiswal⁷, Michael J Rauh¹⁷, Eirini P Papapetrou¹⁸, Samuele G Marro¹⁹, Katherine Y King²⁰

Affiliations

¹ Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Departments of Oncological Sciences and Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Pediatrics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
⁵ Department of Medicine, Queen's University, Kingston, ON, Canada.
⁶ Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, Program in Genetics & Genomics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Graduate School of Biomedical Sciences, Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
¹⁰ Rice University, Houston, TX 77030, USA.
¹¹ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
¹² Division of Hematology Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada; Kingston Health Sciences Centre (KHSC), Kingston, Ontario, Canada.
¹⁵ Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁶ Division of Immunology, Allergy, and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Medicine, Queen's University, Kingston, ON, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada; Kingston Health Sciences Centre (KHSC), Kingston, Ontario, Canada. Electronic address: rauhm@queensu.ca.
¹⁸ Departments of Oncological Sciences and Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: eirini.papapetrou@mssm.edu.
¹⁹ Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: samuele.marro@mssm.edu.
²⁰ Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: katherine.king@bcm.edu.

PMID: 40609533
PMCID: PMC12233156 (available on 2026-06-24)
DOI: 10.1016/j.stem.2025.06.006

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

Katie A Matatall et al. Cell Stem Cell. 2025.

. 2025 Aug 7;32(8):1285-1298.e8.

doi: 10.1016/j.stem.2025.06.006. Epub 2025 Jul 2.

Authors

Affiliations

¹ Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Departments of Oncological Sciences and Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Pediatrics, Jan and Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
⁵ Department of Medicine, Queen's University, Kingston, ON, Canada.
⁶ Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, Program in Genetics & Genomics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Graduate School of Biomedical Sciences, Program in Immunology and Microbiology, Baylor College of Medicine, Houston, TX, 77030, USA.
¹⁰ Rice University, Houston, TX 77030, USA.
¹¹ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
¹² Division of Hematology Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada; Kingston Health Sciences Centre (KHSC), Kingston, Ontario, Canada.
¹⁵ Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁶ Division of Immunology, Allergy, and Rheumatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Medicine, Queen's University, Kingston, ON, Canada; Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada; Kingston Health Sciences Centre (KHSC), Kingston, Ontario, Canada. Electronic address: rauhm@queensu.ca.
¹⁸ Departments of Oncological Sciences and Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: eirini.papapetrou@mssm.edu.
¹⁹ Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: samuele.marro@mssm.edu.
²⁰ Division of Infectious Diseases, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: katherine.king@bcm.edu.

PMID: 40609533
PMCID: PMC12233156 (available on 2026-06-24)
DOI: 10.1016/j.stem.2025.06.006

Erratum in

TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice.
Matatall KA, Wathan TK, Nguyen M, Chen H, McDonald A, Qi G, Belk JA, Florez MA, Le DT, Olarinde T, Vlasschaert C, Buttigieg MM, Fan CW, Carcamo S, Cao R, Kennedy DE 2nd, Maknojia AA, Thatavarty A, Fernandez Sanchez JV, Bouzid H, Veeraragavan S, Crocker S, Goodell MA, Rodriguez A, Jaiswal S, Rauh MJ, Papapetrou EP, Marro SG, King KY. Matatall KA, et al. Cell Stem Cell. 2025 Sep 4;32(9):1475. doi: 10.1016/j.stem.2025.07.011. Epub 2025 Aug 1. Cell Stem Cell. 2025. PMID: 40752497 Free PMC article. No abstract available.

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.

Keywords: Alzheimer’s disease; DNMT3A; TET2; clonal hematopoiesis; inflammation; microglia, peripheral immune cells; myeloid cell activation; phagocytosis.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Florez MA, Tran BT, Wathan TK, DeGregori J, Pietras EM, and King KY (2022). Clonal hematopoiesis: Mutation-specific adaptation to environmental change. Cell Stem Cell 29, 882–904. 10.1016/J.STEM.2022.05.006. - DOI - PMC - PubMed
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TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice

Affiliations

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

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases