Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Institute of Neuroscience, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an, China.
Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China; Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, China.
Exp Neurol. 2021 Feb;336:113506. doi: 10.1016/j.expneurol.2020.113506. Epub 2020 Oct 13.
Overactivated microglia and neuroinflammation are considered to play a crucial role in the progression of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells-2 (TREM2), a type I transmembrane receptor, expressed uniquely by microglia in the brain, is involved in the neuroinflammatory responses of AD. In this study, to further explore the precise effects of TREM2 on neuroinflammation and the underlying mechanisms in AD, we employed a lentiviral-mediated strategy to overexpress TREM2 in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and cultured BV2 cells. Our results showed that TREM2 overexpression rescued cognitive deficits, decreased β-amyloid (Aβ) plaques deposition, reduced synaptic and neuronal loss, as well as ameliorated neuroinflammation. The mechanistic study revealed that these protective effects were likely attributed to inhibition of neuroinflammatory responses through the JAK/STAT/SOCS signaling pathway and subsequent attenuation of pro-inflammatory cytokines. Furthermore, suppression of neuroinflammation might be ascribed to activation of the M2 microglia, as the levels of M2 phenotype markers Arg-1, IL-10 and Ym1 were markedly increased. Similarly, overexpression of TREM2 in BV2 cells also promoted M2 polarization and led to the alleviation of M1 microglial inflammatory responses through JAK/STAT/SOCS signaling pathway, suggesting that TREM2 is an important factor in shifting the microglia from M1 to M2 phenotype. Taken together, our results further provide insights into the role of TREM2 in AD pathogenesis and highlight TREM2 as a potential target against AD.
过度激活的小胶质细胞和神经炎症被认为在阿尔茨海默病（AD）的进展中发挥关键作用。触发受体表达在髓样细胞-2（TREM2），一种 I 型跨膜受体，唯一表达在大脑中的小胶质细胞，参与 AD 的神经炎症反应。在这项研究中，为了进一步探讨 TREM2 在 AD 中对神经炎症的精确作用及其潜在机制，我们采用慢病毒介导的策略在 APPswe/PS1dE9（APP/PS1）转基因小鼠和培养的 BV2 细胞中过表达 TREM2。我们的结果表明，TREM2 的过表达挽救了认知缺陷，减少了 β-淀粉样蛋白（Aβ）斑块沉积，减少了突触和神经元丢失，并改善了神经炎症。机制研究表明，这些保护作用可能归因于通过 JAK/STAT/SOCS 信号通路抑制神经炎症反应，随后减弱促炎细胞因子。此外，神经炎症的抑制可能归因于 M2 小胶质细胞的激活，因为 Arg-1、IL-10 和 Ym1 的 M2 表型标志物水平明显增加。同样，TREM2 在 BV2 细胞中的过表达也通过 JAK/STAT/SOCS 信号通路促进了 M2 极化，并减轻了 M1 小胶质细胞的炎症反应，表明 TREM2 是将小胶质细胞从 M1 表型转变为 M2 表型的重要因素。总之，我们的结果进一步阐明了 TREM2 在 AD 发病机制中的作用，并强调了 TREM2 作为 AD 潜在治疗靶点的重要性。
