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

Hiroshi Hasegawa, Masamichi Nakai, Satoshi Tanimukai, Taizo Taniguchi, Akira Terashima, Toshio Kawamata, Kohji Fukunaga, Eishichi Miyamoto, Kazuyo Misaki, Hideyuki Mukai, Chikako Tanaka

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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 β protein (Aβ), a major component of senile plaques, activated MARCKS through a tyrosine kinase and PKC-δ. We have now identified another Aβ 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 Aβ. Extracellulary regulated kinases, the activities of which were induced by Aβ, 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 Aβ 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.

Original languageEnglish
Pages (from-to)2567-2571
Number of pages5
JournalNeuroReport
Volume12
Issue number11
DOIs
Publication statusPublished - 2001 Aug 8
Externally publishedYes

Keywords

  • Amyloid β protein (Aβ)
  • Extracellular regulated kinase (ERK)
  • Microglia
  • Mitogen-activated protein kinase (MAPK)
  • Myristoylated alanine-rich C kinase substrate (MARCKS)

ASJC Scopus subject areas

  • Neuroscience(all)

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