Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.
Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer's disease.
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DOI：
10.1038/s41467-020-19227-5
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发表时间：
2020-10-23
影响因子：
16.6
通讯作者：
Blurton-Jones M
中科院分区：
文献类型：
--
作者：
McQuade A;Kang YJ;Hasselmann J;Jairaman A;Sotelo A;Coburn M;Shabestari SK;Chadarevian JP;Fote G;Tu CH;Danhash E;Silva J;Martinez E;Cotman C;Prieto GA;Thompson LM;Steffan JS;Smith I;Davtyan H;Cahalan M;Cho H;Blurton-Jones M
TREM2 作为一种骨髓特异性阿尔茨海默病 (AD) 风险基因的发现加速了对小胶质细胞在 AD 中作用的研究。虽然 TREM2 小鼠模型提供了重要的见解，但 TREM2 在人类小胶质细胞中的正常功能和疾病相关功能仍不清楚。为了研究这个问题，我们对同基因、CRISPR 修饰的 TREM2 敲除诱导多能干细胞 (iPSC) 系分化的小胶质细胞进行了分析。通过将转录组学和功能分析与嵌合 AD 小鼠模型相结合，我们发现 TREM2 缺失会降低小胶质细胞的存活率，损害对 APOE 等关键底物的吞噬作用，并抑制 SDF-1α/CXCR4 介导的趋化性，最终导致体内对 β-淀粉样斑块的反应受损。异种移植的人类小胶质细胞的单细胞测序进一步强调了人类 TREM2 敲除小胶质细胞中疾病相关小胶质细胞 (DAM) 反应的丧失，我们通过流式细胞术和免疫组织化学对此进行了验证。总而言之，这些研究揭示了人类 TREM2 生物学的保守和新颖方面，这些方面可能在 AD 的发生和进展中发挥着关键作用。 TREM2 突变会改变患阿尔茨海默病的风险，但人类细胞中潜在风险的机制尚不清楚。在这里，作者使用 iPS 小胶质细胞和嵌合小鼠来强调缺乏 TREM2 的小胶质细胞中生存、吞噬、迁移和转录程序的改变。
The discovery of TREM2 as a myeloid-specific Alzheimer’s disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD. Mutations in TREM2 alter risk for Alzheimer’s disease, though the mechanisms underlying risk in human cells are unclear. Here, the authors use iPS-microglia and chimeric mice to highlight altered survival, phagocytosis, migration, and transcriptional programs in microglia lacking TREM2.
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影响因子：
32.4
作者：
Filipello, Fabia;Morini, Raffaella;Matteoli, Michela
通讯作者：
Matteoli, Michela
影响因子：
4.4
作者：
Daws, MR;Sullam, PM;Seaman, WE
通讯作者：
Seaman, WE
影响因子：
9.8
作者：
De Jager, Philip L.;Ma, Yiyi;Bennett, David A.
通讯作者：
Bennett, David A.
影响因子：
15.1
作者：
Bemiller SM;McCray TJ;Allan K;Formica SV;Xu G;Wilson G;Kokiko-Cochran ON;Crish SD;Lasagna-Reeves CA;Ransohoff RM;Landreth GE;Lamb BT
通讯作者：
Lamb BT
影响因子：
64.8
作者：
Garcia-Prat, Laura;Martinez-Vicente, Marta;Munoz-Canoves, Pura
通讯作者：
Munoz-Canoves, Pura