波士顿儿童医院Christopher A. Walsh团队的最新研究探明了阿尔茨海默病小胶质样细胞中富集的体细胞癌变体驱动炎症和增殖状态。相关论文于2026年4月21日发表在《细胞》杂志上。
阿尔茨海默病（AD）是一种以小胶质细胞介导的神经炎症为特征的神经退行性疾病。311个脑样本的深度（> 1000 ×）面板测序显示，AD脑中癌症驱动基因的体细胞单核苷酸变异（sSNVs）富集，特别是与克隆造血（CH）相关的基因。这些ssnv与克隆扩增相关，并由多个脑区和配对血液中的小胶质样脑巨噬细胞（MLBMs）携带，提示可能的造血起源。
来自另外62个AD和对照脑的单核RNA测序数据显示，AD MLBMs中与CH相关的体细胞拷贝数变异（sCNVs）增加，而单细胞多组学分析表明，携带sSNV和scnv的MLBMs表现出疾病相关小胶质细胞的炎症和增殖转录特征。这些特征在具有TET2、ASXL1和DNMT3A变体的诱导多能干细胞衍生的小胶质样细胞中重现。这些发现表明，MLBMs中的克隆体细胞驱动变异体在AD中富集，可能促进神经炎症和神经退行性变。
附：英文原文
Title: Somatic cancer variants enriched in Alzheimer’s disease microglia-like cells drive inflammatory and proliferative states
Author: August Yue Huang, Zinan Zhou, Maya Talukdar, Liz Enyenihi, Michael B. Miller, Brian Chhouk, Ila Rosen, Mengyue Zheng, Minye Zhou, Averill Yang, Edward Stronge, Madel Durens, Minh Nguyen, Jaejoon Choi, Boxun Zhao, Sattar Khoshkhoo, Junho Kim, Rebecca Andersen, Zheming An, Yuchen Cheng, Javier Ganz, Levan Mekerishvili, Kyle J. Travaglini, Mariano I. Gabitto, Rebecca D. Hodge, Eitan S. Kaplan, Julia A. Belk, Dan Landau, Ed S. Lein, Philip L. De Jager, David A. Bennett, Samuele G. Marro, Eirini P. Papapetrou, Eunjung Alice Lee, Christopher A. Walsh
Issue&Volume: 2026-04-21
Abstract: 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.
DOI: 10.1016/j.cell.2026.03.040
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00341-7