TY - JOUR
T1 - Glutaminase C regulates microglial activation and pro-inflammatory exosome release
T2 - Relevance to the pathogenesis of Alzheimer’s disease
AU - Gao, Ge
AU - Zhao, Shu
AU - Xia, Xiaohuan
AU - Li, Chunhong
AU - Li, Congcong
AU - Ji, Chenhui
AU - Sheng, Shiyang
AU - Tang, Yalin
AU - Zhu, Jie
AU - Wang, Yi
AU - Huang, Yunlong
AU - Zheng, Jialin C.
N1 - Funding Information:
This work was supported in part by research grants from the National Basic Research Program of China (973 Program Grant No. 2014CB965001 to JZ), the State Key Program of the National Natural Science Foundation of China (#81830037), Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002 to JZ), and Research Fund for Young Scientists of the National Natural Science Foundation of China (#81801063 to YW); The project was also supported in part by the NIH, National Institute of Neurological Disorders and Stroke, 1R01NS097195 (JZ), and the National Institute of Mental Health, 2P30MH062261, Developmental (YH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 Gao, Zhao, Xia, Li, Li, Ji, Sheng, Tang, Zhu, Wang, Huang and Zheng.
PY - 2019/5/14
Y1 - 2019/5/14
N2 - Microglial activation is a key pathogenic process at the onset of Alzheimer’s disease (AD). Identifying regulators of microglial activation bears great potential in elucidating causes and mechanisms of AD and determining candidates for early intervention. Previous studies demonstrate abnormal elevation of glutaminase C (GAC) in HIV-infected or immune-activated microglia. However, whether GAC elevation causes microglial activation remains unknown. In this study, we found heightened expression levels of GAC in early AD mouse brain tissues compared with those in control littermates. Investigations on an in vitro neuroinflammation model revealed that GAC is increased in primary mouse microglia following pro-inflammatory stimulation. To model GAC elevation we overexpressed GAC by plasmid transfection and observed that GAC-overexpression shift the microglial phenotype to a pro-inflammatory state. Treatment with BPTES, a glutaminase inhibitor, reversed LPS-induced microglial activation and inflammation. Furthermore, we discovered that GAC overexpression in mouse microglia increased exosome release and changed exosome content, which includes specific packaging of pro-inflammatory miRNAs that activate microglia. Together, our results demonstrate a causal effect of GAC elevation on microglial activation and exosome release, both of which promote the establishment of a pro-inflammatory microenvironment. Therefore, GAC may have important relevance to the pathogenesis of AD.
AB - Microglial activation is a key pathogenic process at the onset of Alzheimer’s disease (AD). Identifying regulators of microglial activation bears great potential in elucidating causes and mechanisms of AD and determining candidates for early intervention. Previous studies demonstrate abnormal elevation of glutaminase C (GAC) in HIV-infected or immune-activated microglia. However, whether GAC elevation causes microglial activation remains unknown. In this study, we found heightened expression levels of GAC in early AD mouse brain tissues compared with those in control littermates. Investigations on an in vitro neuroinflammation model revealed that GAC is increased in primary mouse microglia following pro-inflammatory stimulation. To model GAC elevation we overexpressed GAC by plasmid transfection and observed that GAC-overexpression shift the microglial phenotype to a pro-inflammatory state. Treatment with BPTES, a glutaminase inhibitor, reversed LPS-induced microglial activation and inflammation. Furthermore, we discovered that GAC overexpression in mouse microglia increased exosome release and changed exosome content, which includes specific packaging of pro-inflammatory miRNAs that activate microglia. Together, our results demonstrate a causal effect of GAC elevation on microglial activation and exosome release, both of which promote the establishment of a pro-inflammatory microenvironment. Therefore, GAC may have important relevance to the pathogenesis of AD.
KW - Alzheimer’s disease
KW - Brain inflammation
KW - Exosome
KW - Glutaminase C
KW - Glutaminase inhibitor
KW - Microglia activation
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U2 - 10.3389/fncel.2019.00264
DO - 10.3389/fncel.2019.00264
M3 - Article
C2 - 31316350
AN - SCOPUS:85068571773
VL - 13
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 264
ER -