Glutaminase C Regulates Microglial Activation and Pro-inflammatory Exosome Release: Relevance to the Pathogenesis of Alzheimer's Disease

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 e...

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Bibliographic Details
Published in:Frontiers in cellular neuroscience 2019-06, Vol.13, p.264-264
Main Authors: Gao, Ge, Zhao, Shu, Xia, Xiaohuan, Li, Chunhong, Li, Congcong, Ji, Chenhui, Sheng, Shiyang, Tang, Yalin, Zhu, Jie, Wang, Yi, Huang, Yunlong, Zheng, Jialin C
Format: Article
Language:English
Subjects:
Alzheimer's disease
Brain
brain inflammation
Cardiovascular disease
Dementia
Enzymes
exosome
Glutaminase
glutaminase C
glutaminase inhibitor
HIV
Human immunodeficiency virus
Immunoglobulins
Inflammation
Lipopolysaccharides
Microglia
microglia activation
Neuroscience
Neurotoxicity
Pathogenesis
Phenotypes
Plasmids
Proteins
Transfection
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Summary: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 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.
ISSN:1662-5102
1662-5102
DOI:10.3389/fncel.2019.00264