Glycogen synthase kinase-3β-emediated CCAAT/enhancer-binding protein delta phosphorylation in astrocytes promot es migration and activation of microglia/macrophages

Alzheimer's disease is neuropathologically characterized by the accumulation of amyloid-beta protein into senile plaques that are sites of chronic inflammation involving reactive microglia, astrocytes, and proinflammatory molecules, such as interleukin-1 beta and tumor necrosis factor-alpha. The human CCAAT/enhancerbinding protein (CEBP) delta (CEBPD) is known to be induced in many inflammation-related diseases. In Alzheimer's disease, this protein is responsive to amyloid-beta 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-1 beta through the mitogen-activated protein kinase p38 (MAPKp38) signaling pathway and phosphorylated by glycogen synthase kinase (GSK)-3 beta 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 chemo-attractive factor, and migration factors matrix metalloproteinase-1 and -3 are responsive to GSK3 beta-mediated CEBPD Ser167 phosphorylation. Our results revealed the novel regulation of LiCl on astrocytes and that GSK3 beta-mediated CEBPD phosphorylation in astrocytes plays an important role in the activation of microglia. (c) 2014 The Authors. Published by Elsevier Inc. All rights reserved.