Amyloid β protein activates PKC-δ and induces translocation of myristoylated alanine-rich C kinase substrate (MARCKS) in microglia

The increased accumulation of activated microglia containing amyloid beta protein (A beta) around senile plaques is a common pathological feature in subjects with Alzheimer's disease (AD). Much less is known, however, of intracellular signal transduction pathways for microglial activation in response to A beta. We investigated intracellular signaling in response to A beta stimulation in primary cultured rat microglia. We found that the kinase activity of PKC-delta but not that of PKC-delta or -epsilon is increased by stimulation of microglia with A beta, with a striking tyrosine phosphorylation of PKC-delta. In microglia stimulated with A beta, tyrosine phosphorylation of PKC-delta was evident at the membrane fraction without an overt translocation of PKC-delta. PKC-delta co-immunoprecipitated with MARCKS from microglia stimulated with A beta. A beta induced translocation of MARCKS from the membrane fraction to the cytosolic fraction. Immunocytochemical analysis revealed that phosphorylated MARCKS accumulated in the cytoplasm, particularly at the perinuclear region in microglia treated with A beta. Taken together with our previous observations that A beta -induced phosphorylation of MARCKS and chemotaxis of microglia are inhibited by either tyrosine kinase or PKC inhibitors, our results provide evidence that A beta induces phosphorylation and translocation of MARCKS through the tyrosine kinase-PKC-delta signaling pathway in microglia. (C) 2001 Elsevier Science Ltd. All rights reserved.