Effects of nicotine on APP secretion and Abeta- or CT(105)-induced toxicity.
Several lines of evidence indicated that overexpression or aberrant processing of amyloid precursor protein (APP) is causally related to Alzheimer's disease (AD). Amyloid precursor protein is principally cleaved within the amyloid beta protein domain to release a large soluble ectodomain (APPs), known to have a wide range of trophic functions. The central hypothesis guiding this review is that nicotine may play an important role in APP secretion and protection against toxicity induced by APP metabolic fragments (beta-amyloid [Abeta], carboxyl terminal [CT]). Findings from our experiments have shown that nicotine enhances the release of APPs, which has neurotrophic and neuroprotective activities in concentration-dependent (>50 micromol/L) and time-dependent (>2 hours) manners. In addition, pretreatment of nicotine (>10 micromol/L for 24 hours) partially prevented Abeta or CT(105)-induced cytotoxicity in primary cultured neuron cells, and the effects of nicotine-induced protection were inhibited by the pretreatment with a nicotine alpha-bungarotoxin. Nicotine (>10 micromol/L for 24 hours) partially inhibited CT(105)-induced cytotoxicity when PC12 cells was transfected with CT(105). From these results, we proposed that nicotine or nicotinic receptor agonist treatment might improve the cognitive functions not only by supplementation of cholinergic neurotransmission, but also by protecting Abeta- or CT(105)-induced neurotoxicity probably through the increased release of APPs and the activation of nicotinic receptors.
Department of Pharmacology, College of Medicine, National Creative Research Initiative Centre for Alzheimer's Proteins and Neuroscience Research Institute, Medical Research Centre, Seoul National University, Seoul, South Korea.
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Seo
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Kim
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Kim
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Park
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Jeong
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Lee
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Choi
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Chang
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Rah
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Koo
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Kim
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Suh
D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C409682:amyloid beta-protein precursor CT105; D009538:Nicotine