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.
Keywords:
APP-Tg mice; Alzheimer's disease; NF-κB; gx-50; inflammation; microglia.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / pharmacology*
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Alzheimer Disease / drug therapy*
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Alzheimer Disease / immunology*
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Alzheimer Disease / metabolism
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Amyloid beta-Peptides
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Animals
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Cells, Cultured
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / genetics
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Dinoprostone / immunology
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Dinoprostone / metabolism
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Disease Models, Animal
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Inflammation / immunology
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Mice, Transgenic
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Microglia / drug effects
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Microglia / physiology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Myeloid Differentiation Factor 88 / genetics
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NF-kappa B / metabolism*
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / immunology
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Nitric Oxide Synthase Type II / metabolism
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Rats
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Signal Transduction / drug effects
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TNF Receptor-Associated Factor 6 / genetics
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Toll-Like Receptor 4 / deficiency
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Acrylamides
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Amyloid beta-Peptides
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Interleukin-1beta
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Myeloid Differentiation Factor 88
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NF-kappa B
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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lemairamin
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Nos2 protein, rat
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Ptgs2 protein, rat
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Mitogen-Activated Protein Kinase Kinases
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Dinoprostone