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 (APP) 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 (sAPPalpha) into the conditioned media of cells, with a pattern correlated to the level of acetycholinesterase inhibition. The regulation of APP processing in these conditions is mediated by an indirect cholinergic effect on muscarinic receptors, as demonstrated by inhibition with atropine. We have also followed APP expression and metabolism after 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 sAPPalpha release was unaffected suggesting that enhanced sAPPalpha release by MTF is transitory, nevertheless the sensitivity of cholinergic receptors was unchanged, as indicated by the fact that cholinergic response can be elicited similarly in untreated and treated cells. APP gene expression was unaffected by long-term AChE inhibition suggesting that increased short-term sAPPalpha release does not elicit compensatory effects.
Racchi
M
M
Dept of Experimental and Applied Pharmacology, University of Pavia, Italy. racchi@unipv.it
Sironi
M
M
Caprera
A
A
König
G
G
Govoni
S
S
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004006:Dichlorvos / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008301:Maleimides / Q000494:pharmacology; D009447:Neuroblastoma; D016133:Polymerase Chain Reaction; D011355:Prodrugs / Q000494:pharmacology; D013997:Time Factors; D014236:Trichlorfon / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011355:Prodrugs; D001285:Atropine; D004006:Dichlorvos; D002217:Carbachol; D014236:Trichlorfon; D005954:Glucosephosphate Dehydrogenase; D000110:Acetylcholinesterase; C070515:bisindolylmaleimide I