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 (beta APP) is causally related to Alzheimer's disease. beta APP is principally cleaved within the amyloid beta protein domain to release a large soluble ectodomain (beta APPs) 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 beta APPs through protein kinase C and calcium. Here we have examined whether nicotine can modulate the expression and processing of beta APP in PC12 cells. Treatment of PC12 cells with nicotine increased the release of a carboxyl-terminally truncated, secreted farm of beta APP into the conditioned medium without affecting the expression level of beta APP mRNA. The effect of nicotine on the secretion of beta APPs is concentration (>50 mu M)- 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 beta APPs release by nicotine. However, nicotine did not significantly change the amyloid beta protein secretion from Swedish mutant beta APP-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 beta APPs.