Reduced TREM2 activation in microglia of patients with Alzheimer's disease,FEBS Open Bio

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Reduced TREM2 activation in microglia of patients with Alzheimer's disease
FEBS Open Bio ( IF 2.8 ) Pub Date : 2021-09-15 , DOI: 10.1002/2211-5463.13300
Yuumi Okuzono ₁ , Hiroyuki Sakuma ₂ , Shuuichi Miyakawa ₁ , Masataka Ifuku ₁ , Jonghun Lee ₃ , Debashree Das ₄ , Antara Banerjee ₅ , Yang Zhao ₃ , Koji Yamamoto ₃ , Tatsuya Ando ₃ , Shuji Sato ₂

Affiliation

Loss-of-function variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing Alzheimer's disease (AD). The mechanism through which TREM2 contributes to the disease (TREM2 activation vs inactivation) is largely unknown. Here, we analyzed changes in a gene set downstream of TREM2 to determine whether TREM2 signaling is modified by AD progression. We generated an anti-human TREM2 agonistic antibody and defined TREM2 activation in terms of the downstream expression changes induced by this antibody in microglia developed from human induced pluripotent stem cells (iPSC). Differentially expressed genes (DEGs) following TREM2 activation were compared with the gene set extracted from microglial single nuclear RNA sequencing data of patients with AD, using gene set enrichment analysis. We isolated an anti-TREM2-specific agonistic antibody, Hyb87, from anti-human TREM2 antibodies generated using binding and agonism assays, which helped us identify 300 upregulated and 251 downregulated DEGs. Pathway enrichment analysis suggested that TREM2 activation may be associated with Th2-related pathways. TREM2 activation was lower in AD microglia than in microglia from healthy subjects or patients with mild cognitive impairment. TREM2 activation also showed a significant negative correlation with disease progression. Pathway enrichment analysis of DEGs controlled by TREM2 activity indicated that TREM2 activation in AD may lead to anti-apoptotic signaling, immune response, and cytoskeletal changes in the microglia. We showed that TREM2 activation decreases with AD progression, in support of a protective role of TREM2 activation in AD. In addition, the agonistic anti-TREM2 antibody can be used to identify TREM2 activation state in AD microglia.

中文翻译：

阿尔茨海默病患者小胶质细胞中 TREM2 激活减少

骨髓细胞 2 (TREM2) 上表达的触发受体的功能丧失变异会增加患阿尔茨海默病 (AD) 的风险。 TREM2 导致疾病的机制（TREM2 激活与失活）在很大程度上尚不清楚。在这里，我们分析了 TREM2 下游基因组的变化，以确定 TREM2 信号传导是否因 AD 进展而改变。我们生成了一种抗人 TREM2 激动性抗体，并根据该抗体在人诱导多能干细胞 (iPSC) 发育的小胶质细胞中诱导的下游表达变化来定义 TREM2 激活。使用基因集富集分析，将 TREM2 激活后的差异表达基因 (DEG) 与从小胶质细胞单核 RNA 测序数据中提取的基因集进行比较。我们从使用结合和激动测定产生的抗人 TREM2 抗体中分离出一种抗 TREM2 特异性激动抗体 Hyb87，这帮助我们鉴定了 300 个上调的 DEG 和 251 个下调的 DEG。通路富集分析表明 TREM2 激活可能与 Th2 相关通路有关。 AD 小胶质细胞中的 TREM2 激活低于健康受试者或轻度认知障碍患者的小胶质细胞。 TREM2 激活也显示出与疾病进展呈显着负相关。由 TREM2 活性控制的 DEG 的通路富集分析表明，AD 中 TREM2 的激活可能导致小胶质细胞中的抗凋亡信号、免疫反应和细胞骨架变化。我们发现 TREM2 激活随着 AD 进展而减少，支持 TREM2 激活在 AD 中的保护作用。此外，激动性抗 TREM2 抗体可用于识别 AD 小胶质细胞中的 TREM2 激活状态。

更新日期：2021-11-03

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