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 protein (Abeta) 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 Abeta. We investigated intracellular signaling in response to Abeta stimulation in primary cultured rat microglia. We found that the kinase activity of PKC-delta but not that of PKC-alpha or -epsilon is increased by stimulation of microglia with Abeta, with a striking tyrosine phosphorylation of PKC-delta. In microglia stimulated with Abeta, 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 Abeta. Abeta 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 Abeta. Taken together with our previous observations that Abeta-induced phosphorylation of MARCKS and chemotaxis of microglia are inhibited by either tyrosine kinase or PKC inhibitors, our results provide evidence that Abeta induces phosphorylation and translocation of MARCKS through the tyrosine kinase-PKC-delta signaling pathway in microglia.
Nakai
M
M
Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji 670-0981, Japan.
Tanimukai
S
S
Yagi
K
K
Saito
N
N
Taniguchi
T
T
Terashima
A
A
Kawamata
T
T
Yamamoto
H
H
Fukunaga
K
K
Miyamoto
E
E
Tanaka
C
C
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D004789:Enzyme Activation; D005260:Female; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D017628:Microglia / Q000201:enzymology / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000378:metabolism
D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D011506:Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D014443:Tyrosine; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta