Sayed Faten A, Kodama Lay, Fan Li, Carling Gillian K, Udeochu Joe C, Le David, Li Qingyun, Zhou Lu, Wong Man Ying, Horowitz Rose, Ye Pearly, Mathys Hansruedi, Wang Minghui, Niu Xiang, Mazutis Linas, Jiang Xueqiao, Wang Xueting, Gao Fuying, Brendel Matthew, Telpoukhovskaia Maria, Tracy Tara E, Frost Georgia, Zhou Yungui, Li Yaqiao, Qiu Yue, Cheng Zuolin, Yu Guoqiang, Hardy John, Coppola Giovanni, Wang Fei, DeTure Michael A, Zhang Bin, Xie Lei, Trajnowski John Q, Lee Virginia M Y, Gong Shiaoching, Sinha Subhash C, Dickson Dennis W, Luo Wenjie, Gan Li
Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
Gladstone Institute of Neurological Disease, San Francisco, CA 94107, USA.
Sci Transl Med. 2021 Dec;13(622):eabe3947. doi: 10.1126/scitranslmed.abe3947. Epub 2021 Dec 1.
The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD.
髓系细胞2（TREM2）上表达的触发受体的半合子R47H变体是大脑中的一种小胶质细胞特异性基因，会增加晚发性阿尔茨海默病（AD）的风险。通过对携带R47H突变或常见变体（CV）的AD患者脑组织单细胞核进行转录组分析，我们发现与R47H相关的小胶质细胞亚群具有增强的炎症特征，让人联想到先前鉴定的疾病相关小胶质细胞（DAM）以及TREM2下游信号通路之一AKT的过度激活。我们建立了携带R47H突变或CV的人TREM2杂合敲入的tau蛋白病小鼠模型，发现R47H诱导并加剧了雌性小鼠中TAU介导的空间记忆缺陷。对这些小鼠的小胶质细胞进行单细胞转录组分析还揭示了R47H诱导的转录组变化，这些变化与人类AD大脑中的R47H小胶质细胞有大量重叠，包括促炎细胞因子的显著增加、AKT信号的激活以及一部分DAM特征的升高。用MK - 2206进行药理学AKT抑制在很大程度上逆转了用TAU纤维处理的原代R47H小胶质细胞中增强的炎症特征。在R47H杂合tau蛋白病小鼠中，MK - 2206治疗消除了tau蛋白病依赖性小胶质细胞亚群，并挽救了tau蛋白病诱导的突触丢失。通过揭示在人类和小鼠中保守的R47H突变的疾病增强机制，我们的研究支持将AKT信号抑制剂作为一种治疗AD的小胶质细胞调节策略。
