美国圣路易斯华盛顿大学Marco Colonna研究小组发现，TREM2通过SYK依赖性和非依赖性途径驱动小胶质细胞对淀粉样蛋白-β的反应。相关论文于2022年10月27日发表在《细胞》杂志上。
研究人员表示，遗传学研究强调了小胶质细胞在协调阿尔茨海默病（AD）中的关键作用。粘附在Aβ斑块上的小胶质细胞获得了一种转录特征，即“疾病相关的小胶质细胞”（DAM），它主要来自TREM2-DAP12受体复合物，它通过蛋白酪氨酸激酶SYK传递细胞内信号。与AD高风险相关的人类TREM2R47H变体未能通过SYK激活小胶质细胞。
研究人员发现，SYK缺陷的小胶质细胞不能包裹Aβ斑块，加速了大脑病理和行为缺陷。SYK的缺陷损害了PI3K-AKT-GSK-3β-mTOR途径，使达到DAM特征所需的合成代谢支持失去能力。然而，SYK缺陷的小胶质细胞增殖并推进到DAM的Apoe表达前驱阶段；这一途径依赖于适配器DAP10，它也结合TREM2。因此，小胶质细胞对Aβ的反应涉及非冗余的SYK和DAP10途径。对CLEC7A（一种直接激活SYK的受体）的抗体进行全身给药，可以挽救表达TREM2R47H等位基因小鼠的小胶质细胞激活，为AD免疫疗法提供了新的选择。
附：英文原文
Title: TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
Author: Shoutang Wang, Raki Sudan, Vincent Peng, Yingyue Zhou, Siling Du, Carla M. Yuede, Tingting Lei, Jinchao Hou, Zhangying Cai, Marina Cella, Khai Nguyen, Pietro L. Poliani, Wandy L. Beatty, Yun Chen, Siyan Cao, Kent Lin, Cecilia Rodrigues, Ali H. Ellebedy, Susan Gilfillan, Gordon D. Brown, David M. Holtzman, Simone Brioschi, Marco Colonna
Issue&Volume: 2022/10/27
Abstract: Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer’sdisease (AD). Microglia that adhere to Aβ plaques acquire a transcriptional signature,“disease-associated microglia” (DAM), which largely emanates from the TREM2-DAP12receptor complex that transmits intracellular signals through the protein tyrosinekinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We foundthat SYK-deficient microglia cannot encase Aβ plaques, accelerating brain pathologyand behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3β-mTOR pathway,incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficientmicroglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, whichalso binds TREM2. Thus, microglial responses to Aβ involve non-redundant SYK- andDAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptorthat directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.
DOI: 10.1016/j.cell.2022.09.033
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01252-1