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: Chiung-Yuan Ko, Wen-Ling Wang, Shao-Ming Wang, Yu-Yi Chu, Wen-Chang Chang, Ju-Ming Wang
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 35 Issue 1 Pg. 24-34 (Jan 2014) ISSN: 1558-1497 [Electronic] United States
• PMID: 23993701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Interleukin-1beta
• Tumor Necrosis Factor-alpha
• CCAAT-Enhancer-Binding Protein-delta
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• p38 Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3

Topics

• Alzheimer Disease (etiology, metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Astrocytes (metabolism, physiology)
• CCAAT-Enhancer-Binding Protein-delta (physiology)
• Cell Movement
• Cells, Cultured
• Glycogen Synthase Kinase 3 (physiology)
• Glycogen Synthase Kinase 3 beta
• Humans
• Interleukin-1beta (metabolism, physiology)
• Macrophage Activation (physiology)
• Macrophages (cytology, physiology)
• Mice
• Mice, Transgenic
• Microglia (cytology, physiology)
• Phosphorylation
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (physiology)