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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleNEUROPHARMACOLOGY

Effect of β-Amyloid Peptide 1-42 on the Cytoprotective Action Mediated by α7 Nicotinic Acetylcholine Receptors in Growth Factor-Deprived Differentiated PC-12 Cells

Xinyu D. Li and Jerry J. Buccafusco
Journal of Pharmacology and Experimental Therapeutics November 2003, 307 (2) 670-675; DOI: https://doi.org/10.1124/jpet.103.053785
Xinyu D. Li
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Jerry J. Buccafusco
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Abstract

Brain deposition of β-amyloid peptide (Aβ1-42)-containing senile plaques is a consistent finding in Alzheimer's disease (AD). However, the link between Aβ1-42 and neuronal degeneration remains unclear. It has been reported that Aβ peptides bind with selectivity to α7 nicotinic acetylcholine receptors (α7nAChRs) and that the two proteins are associated in human AD brain tissue. A potential functional interaction between α7nAChRs and Aβ1-42 also has been suggested through the ability of nicotine to inhibit Aβ1-42-induced cytotoxicity. Differentiated PC-12 cells share several features in common with cholinergic basal forebrain neurons. The cells express α7nAChRs, 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 Aβ peptides (Aβ1-42 and Aβ1-40) 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 α7nAChR-selective antagonists α-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 Aβ1-42. 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 α7nAChR antagonists. A concentration-dependent inhibition of the cytoprotective action of nicotine also was produced by cotreatment with Aβ1-42 (1-100 nM), but not with Aβ40 -1. It is possible, therefore, that in AD, as growth factor support to basal forebrain cholinergic neurons declines, the interaction of Aβ peptides with α7nAChRs may enhance toxicity by interfering with an important nicotinic signal for neuronal viability.

Footnotes

  • This study was supported by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs.

  • DOI: 10.1124/jpet.103.053785.

  • ABBREVIATIONS: α7nAChR, α7 nicotinic acetylcholine receptor; NGF, nerve growth factor; MLA, methyllycaconitine; DMEM, Dulbecco's modified Eagle's medium; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenltetrazolium bromide; [Ca2+]i, intracellular calcium concentration; NMDA, N-methyl-d-aspartate.

    • Received May 1, 2003.
    • Accepted July 29, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 2
1 Nov 2003
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Research ArticleNEUROPHARMACOLOGY

Effect of β-Amyloid Peptide 1-42 on the Cytoprotective Action Mediated by α7 Nicotinic Acetylcholine Receptors in Growth Factor-Deprived Differentiated PC-12 Cells

Xinyu D. Li and Jerry J. Buccafusco
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 670-675; DOI: https://doi.org/10.1124/jpet.103.053785

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Research ArticleNEUROPHARMACOLOGY

Effect of β-Amyloid Peptide 1-42 on the Cytoprotective Action Mediated by α7 Nicotinic Acetylcholine Receptors in Growth Factor-Deprived Differentiated PC-12 Cells

Xinyu D. Li and Jerry J. Buccafusco
Journal of Pharmacology and Experimental Therapeutics November 1, 2003, 307 (2) 670-675; DOI: https://doi.org/10.1124/jpet.103.053785
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