title: Gx-50 reduces β-amyloid-induced TNF-α, IL-1β, NO, and PGE2 expression and inhibits NF-κB signaling in a mouse model of Alzheimer's disease.
abstract: Chronic inflammation, which is regulated by overactivated microglia in the brain, accelerates the occurrence and development of Alzheimer's disease (AD). Gx-50 has been investigated as a novel drug for the treatment of AD in our previous studies. Here, we investigated whether gx-50 possesses anti-inflammatory effects in primary rat microglia and a mouse model of AD, amyloid precursor protein (APP) Tg mice. The expression of TNF-α, IL-1β, NO, prostaglandin E2, and the expression of iNOS and COX2 were inhibited by gx-50 in amyloid β (Aβ) treated rat microglia; additionally, microglial activation and the expression of IL-1β, iNOS, and COX2 were also significantly suppressed by gx-50 in APP(+) transgenic mice. Furthermore, gx-50 inhibited the activation of NF-κB and MAPK cascades in vitro and in vivo in APP-Tg mice. Moreover, the expression of TLR4 and its downstream signaling proteins MyD88 and tumor necrosis factor receptor associated factor 6 (TRAF6) was reduced by gx-50 in vitro and in vivo. Interestingly, silencing of TLR4 reduced Aβ-induced upregulation of IL-1β and TRAF6 to levels similar to gx-50 inhibition; moreover, overexpression of TLR4 increased the expression of MyD88 and TRAF6, which was significantly reduced by gx-50. These findings provide strong evidence that gx-50 has anti-inflammatory effects against Aβ-triggered microglial overactivation via a mechanism that involves the TLR4-mediated NF-κBB/MAPK signaling cascade.
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Shi
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Dongli
authors.initials: D
authors.lastname: Liang
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Xie
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Lianyun
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Zhongdong
authors.initials: Z
authors.lastname: Qiao
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D016229:Amyloid beta-Peptides; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000178:Acrylamides; D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C583359:lemairamin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone
keywords: APP-Tg mice; Alzheimer's disease; NF-κB; gx-50; inflammation; microglia