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MOLECULAR PHARMACOLOGY 52:430-436 (1997).

Enhanced Release of Secreted Form of Alzheimer's Amyloid Precursor Protein from PC12 Cells by Nicotine

Seong-Hun Kim, Young-Kyung Kim, Sung-Jin Jeong, Christian Haass, Young-Hoon Kim, and Yoo-Hun Suh

Department of Pharmacology, College of Medicine and Department of Molecular Biology, Neuroscience Research Institute, Seoul National University, Seoul, Korea (S.-H.K., S.-J.J, Y.-H.S.), Department of Neuropsychiatry, Medical College of Inje University, Pusan, Korea (Y.-K.K., Y.-H.K.), and Laboratory for Molecular Biology, Central Institute for Mental Health, University of Heidelberg, Mannheim, Germany (C.H.)

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