PKC and tyrosine kinase involvement in amyloid beta (25-35)-induced chemotaxis of microglia.
Microglia are activated by amyloid beta (Abeta) in vivo and in vitro, and Abeta-activated microglia may be involved in the pathogenesis of Alzheimer's disease (AD). We investigated the mechanism of microglial chemotaxis induced by Abeta (25-35), an active fragment of Abeta. Abeta (25-35) 0.1 and 1 nM stimulated microglial chemotaxis. The protein kinase C (PKC) inhibitors chelerythrine (0.5 and 2 microM), calphostin C (1 microM) and staurospine (10 nM) significantly inhibited the microglial chemotaxis induced by Abeta (25-35) (1 nM). The chemotactic effect of Abeta (25-35) on microglia was desensitized by pretreatment of microglia with 1 ng/ml 12-O-tetradecanoylphorbol 13-acetate (TPA). Pretreatment of cells with Abeta (25-35) (1 nM) also desensitized the chemotactic effect by Abeta (25-35) (1 nM). The desensitization by TPA or Abeta (25-35) was inhibited when staurosporine was present in the pretreatment media. The tyrosine kinase inhibitor herbimycin A (0.1 and 1 microM) significantly inhibited the microglial chemotaxis induced by Abeta (25-35) (1 nM). Based on these observations, it seems likely that PKC and tyrosine kinase are involved in the Abeta-induced chemotaxis of microglia.
Nakai
M
M
Hyogo Institute for Ageing Brain and Cognitive Disorders, Himeji, Japan.
Hojo
K
K
Taniguchi
T
T
Terashima
A
A
Kawamata
T
T
Hashimoto
T
T
Maeda
K
K
Tanaka
C
C
D000470:Alkaloids; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines; D016227:Benzoquinones; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D009281:Naphthalenes / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D016229:Amyloid beta-Peptides; D053119:Benzophenanthridines; D016227:Benzoquinones; D002273:Carcinogens; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D009281:Naphthalenes; D010446:Peptide Fragments; D010617:Phenanthridines; D011809:Quinones; C074636:amyloid beta-protein (25-35); D017828:Rifabutin; C020754:herbimycin; C016299:chelerythrine; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D019311:Staurosporine; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate