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

The increased accumulation of activated microglia containing amyloid beta p rotein (A beta) around senile plaques is a common pathological feature in s ubjects with Alzheimer's disease (AD). Much less is known, however, of intr acellular signal transduction pathways for microglial activation in respons e to A beta. We investigated intracellular signaling in response to A beta stimulation in primary cultured rat microglia. We found that the kinase act ivity of PKC-delta but not that of PKC-delta or -epsilon is increased by st imulation of microglia with A beta, with a striking tyrosine phosphorylatio n of PKC-delta. In microglia stimulated with A beta, tyrosine phosphorylati on of PKC-delta was evident at the membrane fraction without an overt trans location of PKC-delta. PKC-delta co-immunoprecipitated with MARCKS from mic roglia stimulated with A beta. A beta induced translocation of MARCKS from the membrane fraction to the cytosolic fraction. Immunocytochemical analysi s revealed that phosphorylated MARCKS accumulated in the cytoplasm, particu larly at the perinuclear region in microglia treated with A beta. Taken tog ether with our previous observations that A beta -induced phosphorylation o f MARCKS and chemotaxis of microglia are inhibited by either tyrosine kinas e or PKC inhibitors, our results provide evidence that A beta induces phosp horylation and translocation of MARCKS through the tyrosine kinase-PKC-delt a signaling pathway in microglia. (C) 2001 Elsevier Science Ltd. All rights reserved.