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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 (sAPPα) 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 sAPPα release was unaffected suggesting that enhanced sAPPα 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 sAPPα release does not elicit compensatory effects.

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This research was partially funded by MURST Cofin99, ‘Fondo Ateneo Ricerca’ and ‘Progetto Ateneo’ University of Pavia, Telethon E866 to SG.

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Correspondence to M Racchi.

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Racchi, M., Sironi, M., Caprera, A. et al. Short- and long-term effect of acetylcholinesterase inhibition on the expression and metabolism of the amyloid precursor protein. Mol Psychiatry 6, 520–528 (2001).

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  • amyloid precursor protein
  • cholinergic transmission
  • acetylcholinesterase inhibitors
  • neuroblastoma cell lines
  • protein kinase C

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