상세 보기
- Huang, August Yue;
- Zhou, Zinan;
- Talukdar, Maya;
- Enyenihi, Liz;
- Miller, Michael B.;
- ... Kim, Junho;
- 외 29명
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0초록
Alzheimer’s disease (AD) is a neurodegenerative condition characterized by microglia-mediated neuroinflammation. Deep (>1,000×) panel sequencing of 311 brain samples revealed enrichment of somatic single-nucleotide variants (sSNVs) in cancer driver genes in AD brains, especially in genes associated with clonal hematopoiesis (CH). These sSNVs were associated with clonal expansion and carried by both microglia-like brain macrophages (MLBMs) in multiple brain regions as well as paired blood, suggesting a likely hematopoietic origin. Single-nucleus RNA sequencing data from 62 additional AD and control brains revealed increased somatic copy number variants (sCNVs) associated with CH in AD MLBMs, whereas single-cell multi-omic analyses demonstrated that sSNV- and sCNV-carrying MLBMs exhibited inflammatory and proliferative transcriptional signatures characteristic of disease-associated microglia. These signatures were recapitulated in induced pluripotent stem cell-derived microglia-like cells with TET2 , ASXL1 , and DNMT3A variants. These findings suggest that clonal somatic driver variants in MLBMs are enriched in AD, potentially promoting neuroinflammation and neurodegeneration.
키워드
- 제목
- Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states
- 저자
- Huang, August Yue; Zhou, Zinan; Talukdar, Maya; Enyenihi, Liz; Miller, Michael B.; Chhouk, Brian; Rosen, Ila; Zheng, Mengyue; Zhou, Minye; Yang, Averill; Stronge, Edward; Durens, Madel; Nguyen, Minh; Choi, Jaejoon; Zhao, Boxun; Khoshkhoo, Sattar; Kim, Junho; Andersen, Rebecca; An, Zheming; Cheng, Yuchen; Ganz, Javier; Mekerishvili, Levan; Travaglini, Kyle J.; Gabitto, Mariano I.; Hodge, Rebecca D.; Kaplan, Eitan S.; Belk, Julia A.; Landau, Dan; Lein, Ed S.; De Jager, Philip L.; Bennett, David A.; Marro, Samuele G.; Papapetrou, Eirini P.; Lee, Eunjung Alice; Walsh, Christopher A.
- 발행일
- 2026
- 유형
- Article
- 저널명
- Cell