Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein

We have investigated the acute and chronic effect of metrifonate (MTF) and dichlorvos (DDVP), respectively the prodrug and active acetylcholinesterase inhibitor, on the secretory processing of the amyloid precursor protein (A PP) in SH-SY5Y neuroblastoma cells. We demonstrate that the acute treatment of SH-SY5Y cells with both compounds results in an increased secretion of the soluble fragment of APP (sAPP alpha) into the conditioned media of cell s, with a pattern correlated to the level of acetycholinesterase inhibition . The regulation of APP processing in these conditions is mediated by an in direct cholinergic effect on muscarinic receptors, as demonstrated by inhib ition with atropine. We have also followed APP expression and metabolism af ter long-term treatment with metrifonate. Treated cells showed reduced AChE activity after 24, 48 h and also following 7 days of repeated treatment, a time point at which increased AChE expression was detectable. At all time points sAPP alpha release was unaffected suggesting that enhanced sAPP alph a release by MTF is transitory, nevertheless the sensitivity of cholinergic receptors was unchanged, as indicated by the fact that cholinergic respons e can be elicited similarly in untreated and treated cells. APP gene expres sion was unaffected by long-term AChE inhibition suggesting that increased short-term sAPP alpha release does not elicit compensatory effects.