Amyloid-beta peptides induce cell proliferation and macrophage colony-stimulating factor expression via the PI3-kinase/Akt pathway in cultured Ra2 microglial cells.
Alzheimer's disease is characterized by numerous amyloid-beta peptide (Abeta) plaques surrounded by microglia. Here we report that Abeta induces the proliferation of the mouse microglial cell line Ra2 by increasing the expression of macrophage colony-stimulating factor (M-CSF). We examined signal cascades for Abeta-induced M-CSF mRNA expression. The induction of M-CSF was blocked by a phosphatidylinositol 3 kinase (PI3-kinase) inhibitor (LY294002), a Src family tyrosine kinase inhibitor (PP1) and an Akt inhibitor. Electrophoretic mobility shift assays showed that Abeta enhanced NF-kappaB binding activity to the NF-kappaB site of the mouse M-CSF promoter, which was blocked by LY294002. These results indicate that Abeta induces M-CSF mRNA expression via the PI3-kinase/Akt/NF-kappaB pathway.
Ito
Sachiko
S
Department of Basic Gerontology, National Institute for Longevity Sciences, 36-3 Gengo, Morioka-cho, Obu, Aichi 474-8522, Japan.
Sawada
Makoto
M
Haneda
Masataka
M
Fujii
Satoshi
S
Oh-Hashi
Kentaro
K
Kiuchi
Kazutoshi
K
Takahashi
Masahide
M
Isobe
Ken-Ichi
K
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D016229:Amyloid beta-Peptides; D002867:Chromones; D016173:Macrophage Colony-Stimulating Factor; D009025:Morpholines; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D019061:src-Family Kinases; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C074636:amyloid beta-protein (25-35); C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one