TREM2 在调节阿尔茨海默病小胶质细胞病理中的作用位于 CD33 下游。
TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer's Disease.
机构信息
Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; Institute of Biochemistry, Department of Biology, ETH Zürich, 8093 Zürich, Switzerland.
出版信息
Neuron. 2019 Sep 4;103(5):820-835.e7. doi: 10.1016/j.neuron.2019.06.010. Epub 2019 Jul 10.
The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer's disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathology and improved cognition in 5xFAD mice, both of which were abrogated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aβ pathology and neurodegeneration but reduced Iba1 cell numbers, all of which could not be rescued by additional CD33 knockout. RNA-seq profiling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upregulated in 5xFAD;CD33 and downregulated in 5xFAD;TREM2 mice. Differential gene expression in 5xFAD;CD33 microglia depended on the presence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 includes regulation of the IL-1β/IL-1RN axis and a gene set in the "receptor activity chemokine" cluster. Our results should facilitate AD therapeutics targeting these receptors.
小胶质细胞受体 CD33 和 TREM2 与阿尔茨海默病（AD）的风险相关。在这里，我们研究了 CD33 和 TREM2 之间的串扰。我们表明，CD33 的敲除减轻了 5xFAD 小鼠的淀粉样蛋白 β（Aβ）病理学并改善了认知，而 TREM2 的额外敲除则消除了这种作用。在 5xFAD 小鼠中敲除 TREM2 会加剧 Aβ 病理学和神经退行性变，但会减少 Iba1 细胞数量，而这些都不能通过额外的 CD33 敲除来挽救。小胶质细胞的 RNA-seq 分析显示，与吞噬作用和信号转导（IL-6、IL-8、急性期反应）相关的基因在 5xFAD 中上调；CD33 下调；TREM2 小鼠。5xFAD；CD33 小胶质细胞中的差异基因表达取决于 TREM2 的存在，这表明 TREM2 是 CD33 的下游作用。CD33 和 TREM2 之间的串扰包括对 IL-1β/IL-1RN 轴和“受体活性趋化因子”簇中的一组基因的调节。我们的研究结果应有助于针对这些受体的 AD 治疗。
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