Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine.
There is mounting evidence indicating that overexpression or aberrant processing of amyloid precursor protein (betaAPP) is causally related to Alzheimer's disease. betaAPP is principally cleaved within the amyloid beta protein domain to release a large soluble ectodomain (betaAPPs) that has been known to have a wide range of trophic and protective functions. Activation of phospholipase C-coupled receptors has been shown to increase the release of betaAPPs through protein kinase C and calcium. Here we have examined whether nicotine can modulate the expression and processing of betaAPP in PC12 cells. Treatment of PC12 cells with nicotine increased the release of a carboxyl-terminally truncated, secreted form of betaAPP into the conditioned medium without affecting the expression level of betaAPP mRNA. The effect of nicotine on the secretion of betaAPPs is concentration (>50 microM)- and time (>2 hr)-dependent and attenuated by cotreatment with either mecamylamine, a specific nicotinic receptor antagonist, or EGTA, a calcium chelator, indicating calcium entry through the neuronal nicotinic acetylcholine receptor is essential in enhanced betaAPPs release by nicotine. However, nicotine did not significantly change the amyloid beta protein secretion from Swedish mutant betaAPP-transfected PC12 cells. These results imply that nicotinic receptor agonist might be beneficial in the treatment of Alzheimer's disease by not only supplementing the deficient cholinergic neurotransmission but also stimulating the release of betaAPPs.
Kim
S H
SH
Department of Pharmacology, College of Medicine, Neuroscience Research Institute, Seoul National University, Seoul, Korea.
Kim
Y K
YK
Jeong
S J
SJ
Haass
C
C
Kim
Y H
YH
Suh
Y H
YH
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D003470:Culture Media; D004533:Egtazic Acid / Q000494:pharmacology; D007700:Kinetics; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D016716:PC12 Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D003470:Culture Media; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D004533:Egtazic Acid; D008464:Mecamylamine; D009538:Nicotine