ARACHIDONATE METABOLITES AFFECT THE SECRETION OF AN N-TERMINAL FRAGMENT OF ALZHEIMERS-DISEASE AMYLOID PRECURSOR PROTEIN

Amyloid precursor protein (APP) is degraded within the amyloid beta-pr otein (A beta) domain and its large soluble N-terminal fragment (secre ted form of APP: APP(s)) is secreted into the culture media of many ki nds of cells. We report here a quantitative increase in APP(s) secreti on in the medum of human glioblastoma A172 cells grown under serum-fre e conditions. When A172 cells were treated with inhibitors of the arac hidonate cascade, a modulation of APP(s) secretion was observed; the a ddition of small amounts of indomethacin increased secretory cleavage, but higher doses suppressed it. Nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenases, also inhibited APP(s) secretion. These res ults suggest that arachidonate metabolites of the leukotriene pathway may promote APP(s) release upon extracellular signaling via a signal t ransduction pathway, while metabolites of the prostaglandin pathway in hibit APP(s) secretion. (C) 1995 Academic Press, Inc.