Received for publication July 9, 2004.
Revised December 1, 2004.
Accepted for publication December 17, 2004.

MIP-2 inhibits -amyloid peptide (1-42)-mediated hippocampal neuronal apoptosis through activation of mitogen activated protein kinase and phosphatidylinositol 3-kinase signaling pathways

Abstract

-amyloid peptide accumulation in senile plaques in the brain of Alzheimer's disease patients has been considered as a major cause of neuronal death. The present study demonstrated that the CXCR2 ligands, MIP-2, CXCL1, and CXCL8, protected hippocampal neurons against -amyloid (1-42) induced death. MIP-2 activated extracellular signal regulated kinase (ERK1/2) and Akt, and both the mitogen activated protein kinase kinase 1 (MEK1) and phosphatidylinositol 3-kinase (PI3K) inhibitors, PD98059 and wortmannin, reduced the neuroprotective effect of MIP-2. MIP-2 induced weak phosphorylation of ribosomal S6 kinase 1 (RSK1), but remarkable phosphorylation and nuclear translocation of RSK2. MIP-2-induced phosphorylation of RSK2 was inhibited by PD98059 but not by wortmannin. MIP-2 treatment of the neuronal cells resulted in phosphorylation of Bad at both the Ser-112 and Ser-136. The phosphorylation at Ser-112 was blocked by PD98059, whereas the phosphorylation at Ser-136 was blocked by wortmannin. The transcription factor, cyclic AMP response element binding protein (CREB), was phosphorylated by MIP-2 stimulation of the neuronal cells. MIP-2-induced CREB phosphorylation was reduced by both PD98059 and wortmannin. These data demonstrate that both MEK1-ERK1/2 and PI3K-Akt signaling pathways are involved in CXCR2-mediated neuroprotection, and multiple downstream signaling events including RSKs, Bad, and CREB, are activated in this process.

Key words: Chemotactic peptides, MAP Kinase, P38 MAP Kinase, CREB, Excitotoxicity, neurodegeneration