ADDITIVE EFFECTS OF BASIC FIBROBLAST GROWTH-FACTOR AND PHORBOL ESTER ON BETA-AMYLOID PRECURSOR PROTEIN EXPRESSION AND SECRETION

Expression of the beta-amyloid precursor protein (beta-APP), a proteog lycan whose proteolytically derived fragments have been implicated in the neuropathology observed in Alzheimer's disease, is regulated by a variety of stimuli including cytokines, phorbol esters, and growth fac tors. In this study we report the effects of basic fibroblast growth f actor (bFGF) and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), on beta-APP expression and secretion in SKNMC human neuroblastoma cells. Treatment of the cells with bFGF for 24 h increas ed APP promoter activity 200%, cell-associated full-length protein 189 %, and secreted amino-terminal fragments 192% compared to basal levels . Treatment of the cells with PMA for 24 h also up-regulated APP expre ssion and secretion with increases of 170, 112, and 161% being observe d for promoter activity, cell-associated full-length protein, and secr eted amino-terminal fragments, respectively. The effects of bFGF and P MA on the expression and secretion of beta-APP were additive and disti nct in that: (a) co-treatment of the cells with maximally stimulating doses of bFGF and PMA had an additive effect on both induced full-leng th protein expression (242%) and secretion of amino-terminal fragments (311%) compared to basal levels; (b) net levels of full-length protei n expression and secretion induced by bFGF and PMA differed significan tly from each other; and (c) down-regulation of phorbol ester-stimulat ed protein kinase C by pre-treatment of the cells for 24 h with 1 mu M PMA failed to attenuate bFGF-induced transcription or induced secreti on of beta-APP. (C) 1997 Elsevier Science Ltd.