Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA.
Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, CA, 92697, USA.
Nat Commun. 2020 Oct 23;11(1):5370. doi: 10.1038/s41467-020-19227-5.
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.
TREM2 的发现被认为是阿尔茨海默病（AD）的一个髓系特异性风险基因，这加速了人们对小胶质细胞在 AD 中的作用的研究。虽然 TREM2 小鼠模型提供了关键的见解，但 TREM2 在人类小胶质细胞中的正常和与疾病相关的功能仍不清楚。为了研究这个问题，我们对源自同基因 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，损害包括 APOE 在内的关键底物的吞噬作用，并抑制 SDF-1α/CXCR4 介导的趋化作用，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 敲除小胶质细胞中丧失了与疾病相关的小胶质细胞（DAM）反应，我们通过流式细胞术和免疫组织化学验证了这一点。总之，这些研究揭示了人类 TREM2 生物学的既有保守又有新颖的方面，这些方面可能在 AD 的发展和进展中发挥关键作用。
