Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, China.
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
FASEB J. 2019 Sep;33(9):10425-10442. doi: 10.1096/fj.201900527R. Epub 2019 Jun 20.
Triggering receptor expressed in myeloid cells (TREM)2 is a genetic high-risk factor for sporadic Alzheimer's disease (AD) and is considered a potential target for AD diagnosis and therapy, although its role in the different stages of AD remains controversial. We generated an embryonic deletion of Trem2 (whole body deletion) and induced hippocampal- and cortical-specific knockdown of microglial Trem2 at different stages of the AD process in amyloid precursor protein/Psen1 mice by adeno-associated virus (AAV) infection. AAV infection induced microglial Trem2 overexpression in the hippocampus of wild-type (WT) and thymus cell antigen 1-enhanced green fluorescent protein mice. Mice were subjected to ethological and pathologic tests. Whole body genetic deletion of Trem2 exerted different electrophysiological outcomes between different AD pathologic stages, which results from a complex integration of synaptic loss and amyloid aggregation. Interestingly, knockdown of Trem2 at the early-middle stage of AD (2-6 mo) prevents synaptic loss through directly inhibiting microglial phagocytosis, whereas knockdown of Trem2 at the middle-late stage of AD (6-10 mo) accelerates synaptic dysfunction because of more severe amyloid deposition caused by the depression of microglial phagocytosis. Additionally, hippocampal overexpression of Trem2 in WT mice results in significant synaptic impairment. Here, with transgenic technology and electrophysiological assay, we revealed that TREM2 up-regulation promotes microglial phagocytosis equally against synapse and amyloid plaques and eventually results in different outcomes. During the early-middle pathologic stage, TREM2 enhancing microglial phagocytosis mainly causes synaptic loss. However, TREM2 up-regulating microglial phagocytosis gradually supports a positive role when amyloid deposition occupies the leading position at the middle-late pathologic stage. In this study, we highlighted that TREM2 triggers synaptic loss during AD pathology development.-Sheng, L., Chen, M., Cai, K., Song, Y., Yu, D., Zhang, H., Xu, G. Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice.
髓系细胞表达的触发受体 2（TREM2）是散发性阿尔茨海默病（AD）的遗传高危因素，被认为是 AD 诊断和治疗的潜在靶点，尽管其在 AD 不同阶段的作用仍存在争议。我们通过腺相关病毒（AAV）感染在 APP/PS1 小鼠的 AD 进程的不同阶段生成了 Trem2 的胚胎缺失（全身缺失），并诱导了小胶质细胞 Trem2 的海马和皮质特异性敲低。AAV 感染诱导野生型（WT）和胸腺细胞抗原 1-增强型绿色荧光蛋白小鼠海马中的小胶质细胞 Trem2 过表达。小鼠进行行为学和病理测试。Trem2 的全身基因缺失在不同的 AD 病理阶段表现出不同的电生理结果，这是由于突触丢失和淀粉样蛋白聚集的复杂整合。有趣的是，在 AD 的早期-中期（2-6 个月）阶段敲低 Trem2 通过直接抑制小胶质细胞吞噬作用来防止突触丢失，而在 AD 的中期-晚期（6-10 个月）阶段敲低 Trem2 会加速突触功能障碍，因为吞噬作用的抑制导致更严重的淀粉样蛋白沉积。此外，WT 小鼠海马中的 Trem2 过表达导致明显的突触损伤。在这里，我们使用转基因技术和电生理测定，揭示了 TREM2 的上调同等促进小胶质细胞吞噬作用对抗突触和淀粉样斑块，并最终导致不同的结果。在早期-中期病理阶段，TREM2 增强小胶质细胞吞噬作用主要导致突触丢失。然而，当淀粉样蛋白沉积在中期-晚期病理阶段占据主导地位时，TREM2 上调小胶质细胞吞噬作用逐渐发挥积极作用。在这项研究中，我们强调了 TREM2 在 AD 病理发展过程中触发突触丢失。
