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 h 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 and inhibit apoptosis, but 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.

阿尔茨海默病 (AD) 的特征是在脑中积聚细胞外淀粉样蛋白 β (Aβ) 斑块以及由总 tau 和磷酸化 tau 组成的神经元内包涵体（神经原纤维缠结）。还存在营养不良的神经突、突触丧失、神经元死亡和神经胶质增生。AD 基因研究通过识别包括 TREM2 在内的几个风险相关的免疫反应基因，突出了炎症在这种疾病中的重要性。TREM2 与小鼠脑和原代细胞中的基本小胶质细胞功能密切相关，包括吞噬作用、细胞凋亡和对 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 病理积累的关键参与者。然而，关于哪些凋亡或炎症因子在对 Aβ 的反应中依赖 TREM2 的细节仍然缺失，尤其是在人类细胞系中。鉴于这些先前的发现，我们的假设是 TREM2 通过增强吞噬作用和抑制 BCL-2 凋亡蛋白家族和促炎细胞因子来影响对 Aβ 毒性的反应。β₄₂对人小胶质细胞系 HMC3 细胞进行处理，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，24 小时后对 Aβ 的强烈吞噬反应需要 HMC3 细胞中的 TREM2。此外，TREM2 通过激活 Mcl-1/Bim 复合物来抑制 Aβ 诱导的细胞凋亡。TREM2 参与激活 IP-10、MIP-1a 和 IL-8，同时抑制 FGF-2、VEGF 和 GRO。总之，TREM2 在增强 HMC3 细胞中小胶质细胞对 Aβ 毒性的功能反应方面发挥作用。这一新信息表明，寻求激活 TREM2 的治疗策略不仅可以增强吞噬作用和抑制细胞凋亡，还可以抑制有益的炎症因子，