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

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

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, 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 BouzidSurabi Veeraragavan, Susan Crocker, Margaret A. Goodell, Antony Rodriguez, Siddhartha Jaiswal, Michael J. Rauh, Eirini P. Papapetrou, Samuele G. Marro, Katherine Y. King

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4 Scopus citations

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.

Original language	English
Journal	Cell Stem Cell
DOIs	https://doi.org/10.1016/j.stem.2025.06.006
State	Accepted/In press - 2025

Keywords

Alzheimer's disease
clonal hematopoiesis
DNMT3A
inflammation
microglia, peripheral immune cells
myeloid cell activation
phagocytosis
TET2

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10.1016/j.stem.2025.06.006

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Matatall, K. A., Wathan, T. K., Nguyen, M., Chen, H., McDonald, A., Qi, G., Belk, J. A., Florez, M. A., Le, D. T., Olarinde, T., Vlasschaert, C., Buttigieg, M. M., Fan, C. W., Carcamo, S., Cao, R., Kennedy, D. E., Maknojia, A. A., Thatavarty, A., Fernandez Sanchez, J. V., ... King, K. Y. (Accepted/In press). TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice. Cell Stem Cell. https://doi.org/10.1016/j.stem.2025.06.006

@article{1da84915167d40cdbcda881a18777817,

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

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, clonal hematopoiesis, DNMT3A, inflammation, microglia, peripheral immune cells, myeloid cell activation, phagocytosis, TET2",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

doi = "10.1016/j.stem.2025.06.006",

language = "English",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

}

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, 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 2025, 'TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice', Cell Stem Cell. https://doi.org/10.1016/j.stem.2025.06.006

TY - JOUR

T1 - TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice

AU - Matatall, Katie A.

AU - Wathan, Trisha K.

AU - Nguyen, Minh

AU - Chen, Hu

AU - McDonald, Alexandra

AU - Qi, Guantong

AU - Belk, Julia A.

AU - Florez, Marcus A.

AU - Le, Duy T.

AU - Olarinde, Temitope

AU - Vlasschaert, Caitlyn

AU - Buttigieg, Marco M.

AU - Fan, Chih wei

AU - Carcamo, Saul

AU - Cao, Ruoqiong

AU - Kennedy, Daniel E.

AU - Maknojia, Arushana A.

AU - Thatavarty, Apoorva

AU - Fernandez Sanchez, Josaura V.

AU - Bouzid, Hind

AU - Veeraragavan, Surabi

AU - Crocker, Susan

AU - Goodell, Margaret A.

AU - Rodriguez, Antony

AU - Jaiswal, Siddhartha

AU - Rauh, Michael J.

AU - Papapetrou, Eirini P.

AU - Marro, Samuele G.

AU - King, Katherine Y.

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - clonal hematopoiesis

KW - DNMT3A

KW - inflammation

KW - microglia, peripheral immune cells

KW - myeloid cell activation

KW - phagocytosis

KW - TET2

UR - https://www.scopus.com/pages/publications/105009906135

U2 - 10.1016/j.stem.2025.06.006

DO - 10.1016/j.stem.2025.06.006

M3 - Article

AN - SCOPUS:105009906135

SN - 1934-5909

JO - Cell Stem Cell

JF - Cell Stem Cell

ER -

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

Abstract

Keywords

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