Alzheimer's disease (AD) is characterized by the accumulation in the brain of extracellular amyloid β (Aβ) plaques as well as intraneuronal inclusions (neurofibrillary tangles) consisting of total tau and phosphorylated tau. Also present are dystrophic neurites, loss of synapses, neuronal death, and gliosis. AD genetic studies have highlighted the importance of inflammation in this disease by identifying several risk associated immune response genes, including TREM2. TREM2 has been strongly implicated in basic microglia function including, phagocytosis, apoptosis, and the inflammatory response to Aβ in mouse brain and primary cells. These studies show that microglia are key players in the response to Aβ and in the accumulation of AD pathology. However, details are still missing about which apoptotic or inflammatory factors rely on TREM2 in their response to Aβ, especially in human cell lines. Given these previous findings our hypothesis is that TREM2 influences the response to Aβ toxicity by enhancing phagocytosis and inhibiting both the BCL-2 family of apoptotic proteins and pro-inflammatory cytokines. Aβ42 treatment of the human microglial cell line, HMC3 cells, was performed and TREM2 was overexpressed or silenced and the phagocytosis, apoptosis and inflammatory response were evaluated. Results indicate that a robust phagocytic response to Aβ after 24 hours requires TREM2 in HMC3 cells. Also, TREM2 inhibits Aβ induced apoptosis by activating the Mcl-1/Bim complex. TREM2 is involved in activation of IP-10, MIP-1a, and IL-8, while it inhibits FGF-2, VEGF and GRO. Taken together, TREM2 plays a role in enhancing the microglial functional response to Aβ toxicity in HMC3 cells. This novel information suggests that therapeutic strategies that seek to activate TREM2 may not only enhance phagocytosis, but it may also inhibit beneficial inflammatory factors, emphasizing the need to define TREM2-related inflammatory activity in not only mouse models of AD, but also in human AD.

中文翻译：

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TREM2改变HMC3细胞对Aβ42的吞噬，凋亡和炎症反应

阿尔茨海默氏病（AD）的特征是细胞内淀粉样蛋白β（Aβ）斑块以及由总tau和磷酸化tau组成的神经内包裹物（神经原纤维缠结）在大脑中积累。营养不良性神经突，突触丧失，神经元死亡和神经胶质增生也存在。AD遗传学研究通过鉴定包括TREM2在内的几种与风险相关的免疫应答基因，突显了该疾病中炎症的重要性。TREM2与小鼠的大脑和原代细胞中的小胶质细胞的基本功能密切相关，包括吞噬作用，细胞凋亡以及对Aβ的炎症反应。这些研究表明，小胶质细胞是对Aβ的反应和AD病理学积累的关键因素。然而，关于哪些凋亡或炎性因子依赖于TREM2对Aβ的反应（尤其是在人类细胞系中）仍然没有任何细节。鉴于这些先前的发现，我们的假设是TREM2通过增强吞噬作用并抑制凋亡蛋白的BCL-2家族和促炎性细胞因子来影响对Aβ毒性的反应。对人小胶质细胞系HMC3细胞进行Aβ42处理，使TREM2过表达或沉默，并评估吞噬作用，细胞凋亡和炎症反应。结果表明，在24小时后，对Aβ的强大吞噬反应需要HMC3细胞中的TREM2。同样，TREM2通过激活Mcl-1 / Bim复合物抑制Aβ诱导的细胞凋亡。TREM2参与IP-10，MIP-1a和IL-8的活化，同时抑制FGF-2，VEGF和GRO。在一起 TREM2在增强HMC3细胞对Aβ毒性的小胶质细胞功能应答中发挥作用。这一新颖的信息表明，寻求激活TREM2的治疗策略不仅可以增强吞噬作用，而且还可以抑制有益的炎症因子，强调不仅需要在AD的小鼠模型中而且要在人AD中定义与TREM2相关的炎症活性。