特雷姆2
神经炎症
下调和上调
小胶质细胞
TLR4型
MAPK/ERK通路
星形细胞增多症
细胞生物学
肿瘤坏死因子α
信号转导
受体
生物
神经科学
免疫学
炎症
中枢神经系统
基因
生物化学
作者
John Bosco Ruganzu,Xiaoqian Peng,Yingying He,Xiang‐Yuan Wu,Quzhao Zheng,Bo Ding,Chengheng Lin,Hongsong Guo,Zikang Yang,Xiao Zhang,Weina Yang
标识
DOI:10.1016/j.molimm.2021.12.018
摘要
Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that downregulation of TREM2 significantly aggravated AD-related neuropathology including Aβ accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by Aβ1–42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation-related diseases.
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