The microbial alkaloid toxin staurosporine blocks the phorbol ester-induced increase in beta-amyloid precursor protein in PC12 cells.
The amyloid precursor protein (APP) is abnormally cleaved during the progression of Alzheimer's disease, resulting in production of the toxic beta-amyloid peptide, which forms neuritic plaques in the brain. To develop a pharmacological approach for treatment of Alzheimer's disease, natural compounds which may inhibit APP synthesis and/or beta-amyloid production are required. Staurosporine, a toxin isolated from Streptomyces staurospores bacteria, is widely used as a protein kinase C inhibitor in signal transduction research. Using rat pheochromocytoma PC12 sympathetic neurons, which express APP, we characterised staurosporine effect on APP level by western blotting, using an anti-APP monoclonal antibody. PC12 APP levels were increased or decreased upon exposure to either 50-200 nM or 10-20 nM phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), respectively. An apparent relationship was found between the change in APP level and a differential down regulation process of different PKC isoforms. The PMA-induced increase in intracellular APP level was dose-dependently inhibited by staurosporine (natural alkaloid) or GF 109203X (synthetic analogue), protein kinase C (PKC) inhibitors. This inhibition was mainly observed upon treatment of the cells before the exposure to PMA. These results suggest PKC regulation of APP levels in PC12 cells, and provide staurosporine as a leader compound for the development of drugs to control the expression of APP in Alzheimer's research.
Friedman
L M
LM
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.
Matsuda
Y
Y
Lazarovici
P
P
D000470:Alkaloids / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007536:Isomerism; D008301:Maleimides / Q000494:pharmacology*; D016716:PC12 Cells; D011493:Protein Kinase C / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000187:drug effects; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013997:Time Factors
D000470:Alkaloids; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011493:Protein Kinase C; D019311:Staurosporine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate