Li_2010_Exp.Gerontol_45_842

Galantamine (Gal) is an acetylcholinesterase inhibitor and used to treat the symptoms of Alzheimer's disease (AD). Recent studies show that Gal may affect amyloid precursor protein (APP) metabolism and increase release of secretory APPalpha (sAPPalpha). However the effect of Gal on amyloid-beta peptide (Abeta) release and beta-site cleaving enzyme 1 (BACE1) expression is still unknown. Consequently, we investigated the effect of Gal on the level of Abeta and BACE1. In a differentiated human neuroblastoma cell line (SH-SY5Y), Gal (0.3 muM) was found to significantly decrease Abeta release and BACE1 expression following treatment for 6, 12, and 24h. Increasing Gal to 0.9 muM or 10 muM had no further effect. The effect of Gal (0.3 muM for 18h) was maximal on BACE1 expression but not on Abeta secretion. At higher concentration (0.9 muM and 10 muM), Gal had no effect on the level of full-length APP but could still stimulate further decrease in Abeta secretion and release of sAPPalpha. These observations suggested that 0.3 muM Gal exerts its effect on Abeta production by inhibiting BACE1 expression, while 0.9 muM or 10 muM Gal mainly reduces Abeta production by stimulating the non-amyloidogenic pathway to decrease the amount of APP substrate available for beta-secretase cleavage. In addition, alpha7 nicotinic acetylcholine receptor (alpha7nAChR) and multiple second messengers (including PKC, MEK, and p38MAPK) were found to be involved in the regulation of Gal-inhibited Abeta release and BACE1 expression.