Variants of TREM2 are associated with Alzheimer's disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.

中文翻译：

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升高的TREM2基因剂量可重编程小胶质细胞反应性并改善阿尔茨海默氏病模型中的病理表型。

TREM2的变体与阿尔茨海默氏病（AD）相关。为了研究增加TREM2基因剂量是否可以改变疾病发病机理，我们开发了在小胶质细胞中表达人TREM2（BAC-TREM2）的BAC转基因小鼠。我们发现升高的TREM2表达减少了5xFAD小鼠模型中的淀粉样蛋白负担。转录组分析表明，增加TREM2的水平赋予了抢救作用，其中包括抑制多种与疾病相关的小胶质细胞基因的表达和增强下调的神经元基因。有趣的是，5xFAD / BAC-TREM2小鼠表现出与吞噬作用和免疫细胞活化的负调控有关的几个反应性小胶质细胞基因的进一步上调。而且，这些小鼠在斑块相关的小胶质细胞中显示出增强的过程分支和吞噬标记物表达，并减少了神经营养不良。最后，升高的TREM2基因剂量可改善AD模型中的记忆性能。总而言之，我们的研究表明，TREM2表达中由基因组转基因驱动的重编程可重编程小胶质细胞反应性，并改善AD小鼠模型中的神经病理和行为缺陷。