TREM2 agonist-2

TREM2 agonist-2 is an orally active triggering receptor expressed on myeloid cells 2 (TREM2) agonist (EC₅₀<0.05μM)^[1]. The triggering receptor expressed on myeloid cells (TREM) 2 is a member of the immunoglobulin superfamily of receptors and mediates signaling in immune cells via engagement of its co-receptor DNAX-activating protein of 12kDa (DAP12)^[2]_. Activation of TREM2 enhances the phagocytic function of microglia, improving their ability to clear cellular debris, pathogens, and aggregated proteins, while also regulating inflammatory responses and maintaining neuroimmune homeostasis^[3][4]. TREM2 is associated with several neurodegenerative diseases, including Alzheimer’s disease^[5], frontotemporal lobar degeneration, Parkinson’s disease^[6], and multiple sclerosis^[7]. TREM2 agonist-2 is commonly used in research on neurodegenerative diseases^[8].

In vitro, TREM2 agonist-2 (0-100μM; 16h) treatment activated hTREM2 in HEK293 cell, showed an EC₅₀ value <0.05μM^[1].

In vivo, oral gavage of TREM2 agonist-2 (50mg/kg; twice daily; one day) in transgenic mice knock-in hTREM2-CV (Common Variant of TREM2) increased genes associated with the adaptive immune response, innate immune response, microglia function, cytokine signalling, and cell cycle in hippocampus from animals^[1].

References:
[1] Lara C. CZABANIUK, et al. Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use. WO2021226629A1.
[2] Walter J. (2016). The Triggering Receptor Expressed on Myeloid Cells 2: A Molecular Link of Neuroinflammation and Neurodegenerative Diseases. The Journal of biological chemistry, 291(9), 4334–4341.
[3] Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C. M., Galimberti, D., Olivecrona, G., Klein, R. S., Cross, A. H., Otero, K., & Piccio, L. (2015). TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta neuropathologica, 129(3), 429–447.
[4] Hsieh, C. L., Koike, M., Spusta, S. C., Niemi, E. C., Yenari, M., Nakamura, M. C., & Seaman, W. E. (2009). A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. Journal of neurochemistry, 109(4), 1144–1156.
[5] Deming, Y., Li, Z., Benitez, B. A., & Cruchaga, C. (2018). Triggering receptor expressed on myeloid cells 2 (TREM2): a potential therapeutic target for Alzheimer disease?. Expert opinion on therapeutic targets, 22(7), 587–598.
[6] Huang, P., Zhang, Z., Zhang, P., Feng, J., Xie, J., Zheng, Y., Liang, X., Zhu, B., Chen, Z., Feng, S., Wang, L., Lu, J., Liu, Y., & Zhang, Y. (2024). TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson's Disease Mice and LPS-Induced BV2 Cells. Molecular neurobiology, 61(5), 2590–2605.
[7] Cignarella, F., Filipello, F., Bollman, B., Cantoni, C., Locca, A., Mikesell, R., Manis, M., Ibrahim, A., Deng, L., Benitez, B. A., Cruchaga, C., Licastro, D., Mihindukulasuriya, K., Harari, O., Buckland, M., Holtzman, D. M., Rosenthal, A., Schwabe, T., Tassi, I., & Piccio, L. (2020). TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta neuropathologica, 140(4), 513–534.
[8] Yeh, F. L., Hansen, D. V., & Sheng, M. (2017). TREM2, Microglia, and Neurodegenerative Diseases. Trends in molecular medicine, 23(6), 512–533.

TREM2 agonist-2 是一种有口服活性的髓样细胞表达的触发受体2（TREM2）激动剂（EC₅₀<0.05μM）^[1]。髓样细胞表达的触发受体（TREM）2是免疫球蛋白超家族受体的成员，通过与其共受体DNAX激活蛋白12（DAP12）的结合，在免疫细胞中介导信号传导^[2]。TREM2的激活可以促进小胶质细胞的吞噬功能，增强其清除细胞碎片、病原体及聚集蛋白的能力，同时调节炎症反应，维持神经免疫稳态^[3][4]。TREM2与多种神经退行性疾病（如阿尔茨海默病^[5]、额颞叶痴呆、帕金森病^[6]和多发性硬化症^[7]）相关。TREM2 agonist-2通常用于神经退行性疾病的研究^[8]。

体外实验中，TREM2 agonist-2 (0-100μM；16 h)处理可激活HEK293细胞中的hTREM2， EC₅₀值<0.05μM^[1]。

体内实验中，在敲入人类TREM2突变体基因的转基因小鼠中，通过口服灌胃给予TREM2 agonist-2（50mg/kg；每天两次；持续1天），增加了动物海马组织中与适应性免疫反应、先天免疫反应、小胶质细胞功能、细胞因子信号传导以及细胞周期相关的基因表达^[1]。