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.
Highlights
Alzheimer’s disease (AD) is currently the most common neurodegenerative disease worldwide, with an incidence of approximate 6% among population over 65, and around 20% over 80 (Danborg et al, 2014; Reitz and Mayeux, 2014)
We found that the protein expression levels of kidney-type glutaminase (KGA), glutaminase C (GAC), and the pro-inflammatory marker CD86 were not changed in 1 month (1 M) APP/PS1 mouse brain compared with those in 1 M control mouse brains (Figure 1A)
Microglia are the residential macrophages of the central nervous system (CNS), regulating brain inflammation as well as neural and synaptic activity in defense against pathogens, FIGURE 5 | GAC overexpression induces neuroinflammation in a glutamate-independent manner. (A,B) Intracellular glutamate levels (A) and extracellular glutamate levels (B) in control, KGA, and GAC-overexpressed microglia cultures were determined through the Glutamate Assay Kit. (C) mRNA levels of tumor necrosis factor–α (TNF-α), inducible nitric oxide synthase (iNOS), CD206, and Ym1 in microglia treated with different doses of glutamate were determined by qPCR analyses
Summary
Alzheimer’s disease (AD) is currently the most common neurodegenerative disease worldwide, with an incidence of approximate 6% among population over 65, and around 20% over 80 (Danborg et al, 2014; Reitz and Mayeux, 2014) It is the number one cause for dementia in the aged population, imposing significant personal, societal, and economic tolls (WHO 2018 Annual Report). Pathogenesis of AD is known to involve accumulation of amyloid peptides (Aβ) that leads to microglial activation and release of pro-inflammatory mediators such as cytokines, reactive oxygen species, and toxic chemicals. These mediators include several neurotoxic secretory products that may cause severe neurotoxicity and loss of synaptic connections (Tan et al, 1999; Sastre et al, 2006)
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