Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice
Microglial Trem2 induces synaptic impairment at early stage and prevents amyloidosis at late stage in APP/PS1 mice
复制标题
小胶质细胞 Trem2 在 APP/PS1 小鼠中诱导早期突触损伤并预防晚期淀粉样变性
DOI：
10.1096/fj.201900527r
复制
发表时间：
2019-09-01
期刊：
影响因子：
4.8
通讯作者：
Xu, Guangxu
中科院分区：
文献类型：
--
作者：
Sheng, Liang;Chen, Mingming;Xu, Guangxu
髓样细胞表达的触发受体（TREM）2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。我们产生了胚胎缺失Trem 2（全身缺失）和诱导海马和皮质特异性敲低小胶质细胞Trem 2在AD过程的不同阶段，在淀粉样前体蛋白/Psen 1小鼠腺相关病毒（AAV）感染。AAV感染诱导野生型（WT）和胸腺细胞抗原1增强的绿色荧光蛋白小鼠海马中小胶质细胞Trem 2过表达。对小鼠进行行为学和病理学测试。Trem 2的全身基因缺失在AD的不同病理阶段产生不同的电生理结果，这是突触丢失和淀粉样蛋白聚集的复杂整合的结果。有趣的是，在AD的早期-中期阶段（2-6个月）敲低Trem 2通过直接抑制小胶质细胞吞噬作用来防止突触损失，而在AD的中期-晚期阶段（6-10个月）敲低Trem 2由于由小胶质细胞吞噬作用的抑制引起的更严重的淀粉样蛋白沉积而加速突触功能障碍。此外，WT小鼠中Trem 2的海马过表达导致显著的突触损伤。在这里，通过转基因技术和电生理学测定，我们揭示了TREM 2上调促进小胶质细胞对突触和淀粉样斑块的吞噬作用，并最终导致不同的结果。在病理早中期，TREM 2增强小胶质细胞吞噬作用主要导致突触丢失。然而，TREM 2上调小胶质细胞的吞噬功能逐渐支持一个积极的作用时，淀粉样蛋白沉积占主导地位的中晚期病理阶段。在这项研究中，我们强调了TREM 2在AD病理发展过程中引发突触丢失。Sheng，L.，陈美，蔡，K.，宋，Y.，Yu，D.，张洪，Xu，G.小胶质细胞Trem 2在APP/PS1小鼠中诱导早期突触损伤并在晚期预防淀粉样变性。
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.