title: Glycogen synthase kinase-3β-mediated CCAAT/enhancer-binding protein delta phosphorylation in astrocytes promotes migration and activation of microglia/macrophages.
abstract: Alzheimer's disease is neuropathologically characterized by the accumulation of amyloid-β protein into senile plaques that are sites of chronic inflammation involving reactive microglia, astrocytes, and proinflammatory molecules, such as interleukin-1β and tumor necrosis factor-α. The human CCAAT/enhancer-binding protein (CEBP) delta (CEBPD) is known to be induced in many inflammation-related diseases. In Alzheimer's disease, this protein is responsive to amyloid-β and proinflammatory cytokines in astrocytes. However, the functional role of CEBPD in astrocytes remains largely unclear. In this study, we show that CEBPD is upregulated by interleukin-1β through the mitogen-activated protein kinase p38 (MAPKp38) signaling pathway and phosphorylated by glycogen synthase kinase (GSK)-3β at Ser167 in astrocytes. CEBPD in astrocytes is associated with microglia activation and migration in amyloid precursor protein transgenic mice (AppTg) mice. We further identified that the monocyte chemotactic protein-1, a chemoattractive factor, and migration factors matrix metalloproteinase-1 and -3 are responsive to GSK3β-mediated CEBPD Ser167 phosphorylation. Our results revealed the novel regulation of LiCl on astrocytes and that GSK3β-mediated CEBPD phosphorylation in astrocytes plays an important role in the activation of microglia.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Chiung-Yuan
authors.initials: CY
authors.lastname: Ko
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Wang
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Wang
authors.forename: Yu-Yi
authors.initials: YY
authors.lastname: Chu
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000502:physiology*; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D051743:CCAAT-Enhancer-Binding Protein-delta; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
keywords: Alzheimer's disease; Astrocytes; CEBPD; GSK3β; Microglia