Glutaminase C regulates microglial activation and pro-inflammatory exosome release: Relevance to the pathogenesis of Alzheimer’s disease

Ge Gao, Shu Zhao, Xiaohuan Xia, Chunhong Li, Congcong Li, Chenhui Ji, Shiyang Sheng, Yalin Tang, Jie Zhu, Yi Wang, Yunlong Huang, Jialin C. Zheng

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number264
JournalFrontiers in Cellular Neuroscience
Volume13
DOIs
StatePublished - May 14 2019

Keywords

  • Alzheimer’s disease
  • Brain inflammation
  • Exosome
  • Glutaminase C
  • Glutaminase inhibitor
  • Microglia activation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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