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NEUROPHARMACOLOGY

Effect of -Amyloid Peptide 1-42 on the Cytoprotective Action Mediated by 7 Nicotinic Acetylcholine Receptors in Growth Factor-Deprived Differentiated PC-12 Cells

Department of Pharmacology and Toxicology, Alzheimer's Research Center, Medical College of Georgia, and the Veterans Affairs Medical Center, Augusta, Georgia

Brain deposition of -amyloid peptide (A1-42)-containing senile plaques is a consistent finding in Alzheimer's disease (AD). However, the link between A1-42 and neuronal degeneration remains unclear. It has been reported that A peptides bind with selectivity to 7 nicotinic acetylcholine receptors (7nAChRs) and that the two proteins are associated in human AD brain tissue. A potential functional interaction between 7nAChRs and A1-42 also has been suggested through the ability of nicotine to inhibit A1-42-induced cytotoxicity. Differentiated PC-12 cells share several features in common with cholinergic basal forebrain neurons. The cells express 7nAChRs, they require growth factor stimulation for their maintenance and survival, and nicotine protects against cytotoxicity subsequent to growth factor withdrawal. Using these cells as a model system, we designed experiments to more directly determine whether A peptides (A1-42 and A1-40) interfere with a potential nicotinic cytoprotective action and with the ability of nicotine to increase intracellular Ca²⁺. Differentiated PC-12 cells were preloaded with fura 2/acetoxymethyl ester and intracellular free Ca²⁺ levels were determined by fluorescent imaging. Nicotine-induced Ca²⁺ signals were inhibited by pretreatment with the 7nAChR-selective antagonists -bungarotoxin and methyllycaconitine, and they were completely absent in cells maintained in Ca²⁺-free medium. The nicotine response also was blocked by pretreatment with 100 nM A1-42. Nicotine (1-1000 µM) produced a concentration-dependent increase in cell viability in differentiated PC-12 cells that underwent nerve growth factor withdrawal for 24 h. Cell viability was maintained near 100% by 100 µM nicotine. The cytoprotective action of nicotine was efficiently antagonized by cotreatment with 7nAChR antagonists. A concentration-dependent inhibition of the cytoprotective action of nicotine also was produced by cotreatment with A1-42 (1-100 nM), but not with A40 -1. It is possible, therefore, that in AD, as growth factor support to basal forebrain cholinergic neurons declines, the interaction of A peptides with 7nAChRs may enhance toxicity by interfering with an important nicotinic signal for neuronal viability.

Address correspondence to: Dr. Jerry J. Buccafusco, Alzheimer's Research Center, Medical College of Georgia, Augusta, GA 30912-2300. E-mail: jbuccafu{at}mail.mcg.edu

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