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Oligomeric amyloid β facilitates microglial excitotoxicity by upregulating tumor necrosis factor‐α and downregulating excitatory amino acid transporter 2 in astrocytes
Author(s) -
Horiuchi Hiroshi,
Parajuli Bijay,
Kawanokuchi Jun,
Jin Shijie,
Mizuno Tetsuya,
Takeuchi Hideyuki,
Suzumura Akio
Publication year - 2015
Publication title -
clinical and experimental neuroimmunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.297
H-Index - 15
ISSN - 1759-1961
DOI - 10.1111/cen3.12192
Subject(s) - excitotoxicity , microglia , astrocyte , glutamate receptor , neuroglia , biology , microbiology and biotechnology , tumor necrosis factor alpha , neurodegeneration , chemistry , biochemistry , neuroscience , immunology , inflammation , receptor , medicine , central nervous system , disease
Objectives Soluble oligomeric amyloid β ( oA β) directly causes synaptic dysfunction and neuronal death, which are involved in the pathogenesis of Alzheimer's disease. In contrast, several lines of evidence have shown that glia‐mediated excitotoxicity is also involved in the disease progression of Alzheimer's disease. However, it is still unclear how oA β induces glia‐mediated excitotoxicity. Therefore, we tried to clarify the mechanism of oA β‐induced glia‐mediated excitotoxicity using mouse primary cultures. Methods Glial glutamate production was assessed using a colorimetric assay kit. Glial production of tumor necrosis factor‐α ( TNF ‐α) was evaluated using a specific enzyme‐linked immunosorbent assay kit. Microglial survival was examined using the MTS assay. mRNA and protein expression levels of excitatory amino acid transporter 2 were determined using quantitative polymerase chain reaction and western blotting, respectively. Results We showed that oA β‐stimulation induces glutamate release from astrocyte/microglia co‐cultures, but not from single culture of astrocytes or microglia. oA β increased TNF ‐α release from astrocytes, but not from microglia, and the astrocyte‐derived TNF ‐α enhanced glutamate release from microglia. TNF ‐α elongated microglial survival and triggered sustained microglial glutamate release in a positive feedback mechanism through TNF ‐α receptor 1. Furthermore, treatment of oA β decreased astrocytic expression of excitatory amino acid transporter 2, which plays a pivotal role in homeostasis of the extracellular glutamate level. Conclusions The present findings suggest that oA β contributes to glia‐mediated excitotoxicity through the two‐hit mechanism by suppressing astrocytic glutamate uptake through excitatory amino acid transporter 2 and enhancing microglial glutamate release, and triggers chronic glial neuroinflammation through the TNF ‐α/ TNF ‐α receptor 1 positive feedback loop in Alzheimer's disease.