Effect of amyloid peptides on the increase in TrkA receptor expression induced by nicotine in vitro and in vivo.

The ability of nicotine to induce a cytoprotective or neuroprotective action occurs through several downstream mechanisms. One possibility is that the drug increases the expression of tyrosine kinase A (TrkA) nerve growth factor (NGF) receptors. Certain beta-amyloid peptides (e.g., Abeta1-42) have been shown to bind with high affinity to alpha7 nicotinic receptors and thus interfere with a potentially neurotrophic influence. Treatment of differentiated PC-12 cells with nicotine produced a concentration-dependent increase in cell-surface TrkA receptors that occurred concomitantly with cytoprotection. The effect of nicotine was blocked by either of the alpha7 receptor antagonists alpha-bungarotoxin (alpha-BTX) or methyllycaconatine. The cytoprotective action of nicotine also was inhibited by pretreatment with 10-100 nM Abeta1-42. Nicotine also was administered (four injections of 30 microg, spaced evenly over 24 h) to rats by direct injection into a lateral cerebral ventricle. Brain TrkA expression was increased significantly in hippocampus and entorhinal cortex (up to 32% above control), with no changes found in cerebral cortex or hypothalamus. The nicotine-induced increases in TrKA expression in hippocampus and entorhinal cortex were significantly inhibited by 10 microg alpha-BTXor by 10 nmol Abeta1-42. Therefore, physiologically relevant concentrations of Abeta1-42 can prevent nicotine-induced TrkA receptor expression in brain regions containing cholinergic neurons susceptible to the neurotoxicity associated with Alzheimer's disease.