Effects of nicotine on APP secretion and Aβ- or CT105-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 β 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 (β-amyloid [Aβ], 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 μmol/L) and time-dependent (>2 hours) manners. In addition, pretreatment of nicotine (>10 μmol/L for 24 hours) partially prevented Aβ or CT105-induced cytotoxicity in primary cultured neuron cells, and the effects of nicotine-induced protection were inhibited by the pretreatment with a nicotine α-bungarotoxin. Nicotine (>10 μmol/L for 24 hours) partially inhibited CT105-induced cytotoxicity when PC12 cells was transfected with CT105. 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 Aβ- or CT105-induced neurotoxicity probably through the increased release of APPs and the activation of nicotinic receptors.