Increased cysteinyl-tRNA synthetase drives neuroinflammation in Alzheimer’s disease  

作　　者：Xiu-Hong Qi Peng Chen Yue-Ju Wang Zhe-Ping Zhou Xue-Chun Liu Hui Fang Chen-Wei Wang Ji Liu Rong-Yu Liu Han-Kui Liu Zhen-Xin Zhang Jiang-Ning Zhou 

机构地区：[1]Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230027,China [2]Institute of Brain Science,The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China [3]Department of Geriatrics,The First Affiliated Hospital of Soochow University,Suzhou 215006,China [4]Department of Neurology,Hefei Hospital Affiliated to Anhui Medical University,Hefei 230011,China [5]Anhui Institute of Pediatric Research,Anhui Provincial Children’s Hospital,Hefei 230051,China [6]School of Basic Medical Sciences,Anhui Medical University,Hefei 230032,China [7]National Engineering Laboratory for Brain-Inspired Intelligence Technology and Application,School of Information Science and Technology,and The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei 230027,China [8]Department of Respiratory and Critical Care,The First Affiliated Hospital of Anhui Medical University,Hefei 230022,China [9]Key Laboratory of Diseases and Genomes,BGI-Genomics,BGI-Shenzhen,Shenzhen 518000,China [10]Department of Neurology and Clinical Epidemiology Unit,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing 100007,China [11]Center for Excellence in Brain Science and Intelligence Technology,Chinese Academy of Sciences,Shanghai 200031,China

出　　处：《Translational Neurodegeneration》2024年第1期1064-1082,共19页转化神经变性病(英文)

基　　金：supported by the National Natural Science Foundation of China(32030046,32000716);the Strategic Priority Research Program of the Chinese Academy of Science(XDB32020200);the National Key R&D Program of China(2016YFC1305900);the STI2030-Major Projects(2022ZD0205202);Anhui Province University Scientific Research Project(KJ2021A0212).

摘　　要：Background Microglia-mediated neuroinflammation in Alzheimer’s disease(AD)is not only a response to pathophysiological events,but also plays a causative role in neurodegeneration.Cytoplasmic cysteinyl-tRNA synthetase(CARS)is considered to be a stimulant for immune responses to diseases;however,it remains unknown whether CARS is involved in the pathogenesis of AD.Methods Postmortem human temporal cortical tissues at different Braak stages and AD patient-derived serum samples were used to investigate the changes of CARS levels in AD by immunocytochemical staining,real-time PCR,western blotting and ELISA.After that,C57BL/6J and APP/PS1 transgenic mice and BV-2 cell line were used to explore the role of CARS protein in memory and neuroinflammation,as well as the underlying mechanisms.Finally,the associations of morphological features among CARS protein,microglia and dense-core plaques were examined by immu-nocytochemical staining.Results A positive correlation was found between aging and the intensity of CARS immunoreactivity in the temporal cortex.Both protein and mRNA levels of CARS were increased in the temporal cortex of AD patients.Immunocytochemical staining revealed increased CARS immunoreactivity in neurons of the temporal cortex in AD patients.Moreover,overexpression of CARS in hippocampal neurons induced and aggravated cognitive dysfunction in C57BL/6J and APP/PS1 mice,respectively,accompanied by activation of microglia and the TLR2/MyD88 signaling pathway as well as upregulation of proinflammatory cytokines.In vitro experiments showed that CARS treatment facilitated the production of proinflammatory cytokines and the activation of the TLR2/MyD88 signaling pathway of BV-2 cells.The accumulation of CARS protein occurred within dense-core Aβplaques accompanied by recruitment of ameboid microglia.Significant upregulation of TLR2/MyD88 proteins was also observed in the temporal cortex of AD.Conclusions The findings suggest that the neuronal CARS drives neuroinflammation and induces memory deficits,which migh

关 键 词：Cysteinyl-tRNA synthetase Alzheimer’s disease NEUROINFLAMMATION MICROGLIA TLR2 

分 类 号：R749.16[医药卫生—神经病学与精神病学]