| Title: | TET2-mutant myeloid cells mitigate Alzheimer's disease progression via CNS infiltration and enhanced phagocytosis in mice |
| Journal: | Cell Stem Cell |
| Published: | 2 Jul 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40609533/ |
| DOI: | https://doi.org/10.1016/j.stem.2025.06.006 |
Publication 16516
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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.</p>
20 Keywords
- Alzheimer Disease
- Animals
- Brain
- Central Nervous System
- Clonal Hematopoiesis
- DNA Methyltransferase 3A
- DNA-Binding Proteins
- Dioxygenases
- Disease Models, Animal
- Disease Progression
- Female
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Microglia
- Mutation
- Myeloid Cells
- Phagocytosis
- Proto-Oncogene Proteins
29 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
- Surabi Veeraragavan
- Susan Crocker
- Margaret A Goodell
- Antony Rodriguez
- Siddhartha Jaiswal
- Michael J Rauh
- Eirini P Papapetrou
- Samuele G Marro
- Katherine Y King
1 Application
| Application ID | Title |
|---|---|
| 101583 | The role of clonal hematopoiesis of indeterminate potential in infection and cancer risk |
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