Effects of galantamine on β-amyloid release and beta-site cleaving enzyme 1 expression in differentiated human neuroblastoma SH-SY5Y cells.
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.
Li
Qianqian
Q
Department of Neurology, the First Affiliated Hospital of Harbin Medical University, PR China.
Wu
Donglai
D
Zhang
Liming
L
Zhang
Yan
Y
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005702:Galantamine / Q000008:administration & dosage*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D015290:Second Messenger Systems; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human