The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), 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)–TREM2, 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 TREM2 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.

中文翻译：

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AD 相关的 R47H-TREM2 突变通过 AKT 过度激活诱导疾病增强的小胶质细胞状态

骨髓细胞 2 ( TREM2 ) 上表达的触发受体的半合子 R47H 变体是大脑中小胶质细胞特异性基因，会增加患迟发性阿尔茨海默病 (AD) 的风险。通过对携带 R47H 突变或常见变异 (CV)-TREM2 的 AD 患者脑组织中的单核进行转录组分析，我们发现 R47H 相关的小胶质细胞亚群具有增强的炎症特征，让人想起之前发现的疾病相关小胶质细胞 (DAM) AKT 过度激活，AKT 是 TREM2 下游信号通路之一。我们建立了带有 R47H 突变或 CV 的人类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。对这些小鼠小胶质细胞的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 小胶质细胞有很大的重叠，包括促炎细胞因子的强劲增加、AKT 信号传导的激活以及 DAM 特征子集的升高。MK-2206 的药理学 AKT 抑制在很大程度上逆转了用 TAU 原纤维处理的原代 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 蛋白病诱导的突触损失。通过揭示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 AKT 信号传导抑制剂作为治疗 AD 的小胶质细胞调节策略。