TSPO deficiency accelerates amyloid pathology and neuroinflammation by impairing microglial phagocytosis
TSPO deficiency accelerates amyloid pathology and neuroinflammation by impairing microglial phagocytosis
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TSPO 缺乏通过损害小胶质细胞吞噬作用加速淀粉样蛋白病理和神经炎症
DOI：
10.1016/j.neurobiolaging.2021.06.020
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发表时间：
2021
影响因子：
4.2
通讯作者：
Jianmin Zhang
中科院分区：
文献类型：
--
作者：
Hanxiao Zhang;Huai;Fei Gao;Jia Yang;Yi Xu;Yi Fu;Menghua Cai;Xue Zhang;Qi Yang;Kexin Tong;Yu Hu;Hui Chen;Chao Ma;Wei He;Jianmin Zhang
越来越多的证据表明，炎症和免疫功能障碍是阿尔茨海默病（AD）发病机制的核心。线粒体转运蛋白（18 kDa） （TSPO）在小胶质细胞和星形胶质细胞对炎症刺激的反应中高度上调。然而，迄今为止，TSPO在AD发病机制中的生物学作用尚未确定。在本研究中，我们发现AD患者和AD模型小鼠脑组织中TSPO表达上调。缺乏TSPO的APP/PS1小鼠大脑中Aβ1-40和Aβ1-42肽水平显著升高，Aβ斑块增多，小胶质细胞活化增强。体外培养的tspo缺陷小胶质细胞对a β肽的吞噬能力显著下降，对a β肽的反应产生更多的促炎细胞因子（TNF-α和IL-1β）。我们的研究结果表明，TSPO对AD的神经炎症和Aβ发病机制具有保护作用。TSPO可能是开发治疗或预防神经炎性疾病药物的潜在靶点。
Increasing evidence has placed inflammation and immune dysfunction at the center of the pathogenesis of Alzheimer's disease (AD). The mitochondrial protein translocator protein (18 kDa) (TSPO) is highly upregulated in microglia and astrocytes in response to inflammatory stimulation. However, the biological action of TSPO in the pathogenesis of AD has not been determined to date. In this study, we showed that TSPO expression was upregulated in brain tissues from AD patients and AD model mice. APP/PS1 mice lacking TSPO generated significantly higher levels of Aβ1-40and Aβ1-42peptides and more Aβ plaques, as well as enhanced microglial activation, in the brain. TSPO-deficient microglia cultured in vitro showed a significant decrease in the ability to phagocytose Aβ peptides or latex beads and generated more proinflammatory cytokines (TNF-α and IL-1β) in response to Aβ peptides. Our findings suggest that TSPO has protective functions against neuroinflammation and Aβ pathogenesis in AD. TSPO may be a potential drug target for the development of drugs that have therapeutic or preventive effects in neuroinflammatory diseases.