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 APPα (sAPPα). However the effect of Gal on amyloid-β peptide (Aβ) release and β-site cleaving enzyme 1 (BACE1) expression is still unknown. Consequently, we investigated the effect of Gal on the level of Aβ and BACE1. In a differentiated human neuroblastoma cell line (SH-SY5Y), Gal (0.3 μM) was found to significantly decrease Aβ release and BACE1 expression following treatment for 6, 12, and 24h. Increasing Gal to 0.9 μM or 10 μM had no further effect. The effect of Gal (0.3 μM for 18h) was maximal on BACE1 expression but not on Aβ secretion. At higher concentration (0.9 μM and 10 μM), Gal had no effect on the level of full-length APP but could still stimulate further decrease in Aβ secretion and release of sAPPα. These observations suggested that 0.3 μM Gal exerts its effect on Aβ production by inhibiting BACE1 expression, while 0.9 μM or 10 μM Gal mainly reduces Aβ production by stimulating the non-amyloidogenic pathway to decrease the amount of APP substrate available for β-secretase cleavage. In addition, α7 nicotinic acetylcholine receptor (α7nAChR) and multiple second messengers (including PKC, MEK, and p38MAPK) were found to be involved in the regulation of Gal-inhibited Aβ release and BACE1 expression.
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