Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amyloid beta-Peptides / pharmacology*
-
Animals
-
Cell Proliferation / drug effects
-
Cells, Cultured
-
Chromones / pharmacology
-
Gene Expression / drug effects
-
Macrophage Colony-Stimulating Factor / genetics
-
Macrophage Colony-Stimulating Factor / metabolism*
-
Mice
-
Microglia / drug effects
-
Microglia / enzymology
-
Microglia / metabolism*
-
Morpholines / pharmacology
-
Peptide Fragments / pharmacology*
-
Phosphatidylinositol 3-Kinases / physiology*
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors / pharmacology
-
Protein Serine-Threonine Kinases / antagonists & inhibitors
-
Protein Serine-Threonine Kinases / physiology*
-
Proto-Oncogene Proteins / antagonists & inhibitors
-
Proto-Oncogene Proteins / physiology*
-
Proto-Oncogene Proteins c-akt
-
Pyrazoles / pharmacology
-
Pyrimidines / pharmacology
-
RNA, Messenger / metabolism
-
Signal Transduction
-
src-Family Kinases / antagonists & inhibitors
Substances
-
4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine
-
Amyloid beta-Peptides
-
Chromones
-
Morpholines
-
Peptide Fragments
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins
-
Pyrazoles
-
Pyrimidines
-
RNA, Messenger
-
amyloid beta-protein (25-35)
-
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
-
Macrophage Colony-Stimulating Factor
-
src-Family Kinases
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt