Microglial signaling by amyloid beta protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS.

Myristoylated alanine-rich C kinase substrate (MARCKS), an acidic protein associated with cell motility and phagocytosis, is activated upon phosphorylation by protein kinase C (PKC) and proline-directed protein kinases. In Alzheimer disease (AD), activated microglia expressing MARCKS migrates around senile plaques. We reported that amyloid beta protein (A beta), a major component of senile plaques, activated MARCKS through a tyrosine kinase and PKC-delta. We have now identified another A beta signaling pathway through a mitogen-activated protein kinase (MAPK) involved in the phosphorylation of MARCKS and analysed cross-talk between PKC and MAPK pathways in primary cultured rat microglia. A selective inhibitor for MAPK kinase, PD098059, significantly inhibited the phosphorylation of MARCKS induced by A beta. Extracellulary regulated kinases, the activities of which were induced by A beta, directly phosphorylated a recombinant MARCKS in vitro. The MAPK pathway was sensitive to wortmannin, but not to a PKC inhibitor or to tyrosine kinase inhibitors. The activation of PKC by A beta was not sensitive to wortmannin. Our findings suggest involvement of the MAPK pathway through phosphoinositol 3-kinase in the phosphorylation of MARCKS in rat cultured microglia, an event may be associated with mechanisms activating microglia in AD.