Glycogen synthase kinase-3ß-mediated CCAAT/enhancer-binding protein delta phosphorylation in astrocytes promotes migration and activation of microglia/macrophages.

Alzheimer's disease is neuropathologically characterized by the accumulation of amyloid-ß protein into senile plaques that are sites of chronic inflammation involving reactive microglia, astrocytes, and proinflammatory molecules, such as interleukin-1ß 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-ß 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-1ß through the mitogen-activated protein kinase p38 (MAPKp38) signaling pathway and phosphorylated by glycogen synthase kinase (GSK)-3ß 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 GSK3ß-mediated CEBPD Ser167 phosphorylation. Our results revealed the novel regulation of LiCl on astrocytes and that GSK3ß-mediated CEBPD phosphorylation in astrocytes plays an important role in the activation of microglia.