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.
Li
Xinyu D
XD
Alzheimer's Research Center, Medical College of Georgia, Augusta, GA, USA.
Arias
Esperanza
E
Jonnala
Ramamohana R
RR
Mruthinti
Shyamala
S
Buccafusco
Jerry J
JJ
D000157:Aconitine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism*; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); C054634:methyllycaconitine; D009538:Nicotine; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D000157:Aconitine