Allosteric Modulator Desformylflustrabromine Relieves the Inhibition of α2β2 and α4β2 Nicotinic Acetylcholine Receptors by β-Amyloid1–42 Peptide



Nicotinic acetylcholine receptors (nAChRs) are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer’s disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of β amyloid (Aβ1–42) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for α4β2 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the α2β2 nAChR subtype was not known. The action of dFBr was tested on α2β2 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the α2β2 receptor. Next we tested whether dFBr had any effect on the previously known block of both the α4β2 and α2β2 receptors by Aβ1–42. We found that the functional blockade of ACh-induced currents in oocytes expressing α4β2 and α2β2 receptors by Aβ1–42 was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both α4β2 and α2β2 subtypes of nAChRs and that it also relieves the blockade of these receptors by Aβ1–42. This study demonstrates that PAMs for the non-α7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders.


Alzheimer’s disease (AD) Beta amyloid (Aβ1–42Desformylflustrabromine (dFBr) Electrophysiology Nicotinic acetylcholine receptors (nAChRs) Positive allosteric modulators (PAMs) 


  1. Court J, Martin-Ruiz C, Piggott M, Spurden D, Griffiths M, Perry E (2001) Nicotinic receptor abnormalities in Alzheimer’s disease. Biol Psychiatry 49(3):175–184PubMedCrossRefGoogle Scholar
  2. Coyle JT, Price DL, DeLong MR (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219(4589):1184–1190PubMedCrossRefGoogle Scholar
  3. Dineley KT, Bell KA, Bui D, Sweatt JD (2002) beta-Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Biol Chem 277(28):25056–25061PubMedCrossRefGoogle Scholar
  4. Dougherty JJ, Wu J, Nichols RA (2003) beta-Amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J Neurosci 23(17):6740–6747PubMedGoogle Scholar
  5. Flores CM, Rogers SW, Pabreza LA, Wolfe BB, Kellar KJ (1992) A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment. Mol Pharmacol 41(1):31–37PubMedGoogle Scholar
  6. Fu W, Jhamandas JH (2003) beta-Amyloid peptide activates non-alpha7 nicotinic acetylcholine receptors in rat basal forebrain neurons. J Neurophysiol 90(5):3130–3136PubMedCrossRefGoogle Scholar
  7. Gay EA, Yakel JL (2007) Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening. J Physiol 584(Pt 3):727–733PubMedCrossRefGoogle Scholar
  8. Gopalakrishnan M, Monteggia LM, Anderson DJ et al (1996) Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor. J Pharmacol Exp Ther 276(1):289–297PubMedGoogle Scholar
  9. Grassi F, Palma E, Tonini R, Amici M, Ballivet M, Eusebi F (2003) Amyloid beta(1–42) peptide alters the gating of human and mouse alpha-bungarotoxin-sensitive nicotinic receptors. J Physiol 547(Pt 1):147–157PubMedCrossRefGoogle Scholar
  10. Huang Y, Liu XQ, Wyss-Coray T, Brecht WJ, Sanan DA, Mahley RW (2001) Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 98(15):8838–8843PubMedCrossRefGoogle Scholar
  11. Jones S, Sudweeks S, Yakel JL (1999) Nicotinic receptors in the brain: correlating physiology with function. Trends Neurosci 22(12):555–561PubMedCrossRefGoogle Scholar
  12. Kim JS, Padnya A, Weltzin M, Edmonds BW, Schulte MK, Glennon RA (2007) Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator. Bioorg Med Chem Lett 17(17):4855–4860PubMedCrossRefGoogle Scholar
  13. Lamb PW, Melton MA, Yakel JL (2005) Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by beta-amyloid1–42 peptide. J Mol Neurosci 27(1):13–21PubMedCrossRefGoogle Scholar
  14. Levin ED, Simon BB (1998) Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology (Berl) 138(3–4):217–230CrossRefGoogle Scholar
  15. Lindstrom J (1996) Neuronal nicotinic acetylcholine receptors. Ion Channels 4:377–450PubMedGoogle Scholar
  16. Lindstrom J, Anand R, Gerzanich V, Peng X, Wang F, Wells G (1996) Structure and function of neuronal nicotinic acetylcholine receptors. Prog Brain Res 109:125–137PubMedCrossRefGoogle Scholar
  17. Liu Q, Kawai H, Berg DK (2001) beta-Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci USA 98(8):4734–4739PubMedCrossRefGoogle Scholar
  18. Liu Q, Huang Y, Xue F et al (2009) A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. J Neurosci 29(4):918–929PubMedCrossRefGoogle Scholar
  19. Lysek N, Rachor E, Lindel T (2002) Isolation and structure elucidation of deformylflustrabromine from the North Sea bryozoan Flustra foliacea. Z Naturforsch C 57(11–12):1056–1061PubMedGoogle Scholar
  20. McQuiston AR, Madison DV (1999) Nicotinic receptor activation excites distinct subtypes of interneurons in the rat hippocampus. J Neurosci 19(8):2887–2896PubMedGoogle Scholar
  21. Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE (1994) Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science 264(5160):850–852PubMedCrossRefGoogle Scholar
  22. Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61(1):75–111PubMedCrossRefGoogle Scholar
  23. Perry EK, Perry RH, Smith CJ et al (1986) Cholinergic receptors in cognitive disorders. Can J Neurol Sci 13(4 Suppl):521–527PubMedGoogle Scholar
  24. Peters L, Wright AD, Kehraus S, Gundisch D, Tilotta MC, Konig GM (2004) Prenylated indole alkaloids from Flustra foliacea with subtype specific binding on NAChRs. Planta Med 70(10):883–886PubMedCrossRefGoogle Scholar
  25. Pettit DL, Shao Z, Yakel JL (2001) beta-Amyloid(1–42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci 21(1):RC120PubMedGoogle Scholar
  26. Picciotto MR, Zoli M, Lena C et al (1995) Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374(6517):65–67PubMedCrossRefGoogle Scholar
  27. Sala F, Mulet J, Reddy KP et al (2005) Potentiation of human alpha4beta2 neuronal nicotinic receptors by a Flustra foliacea metabolite. Neurosci Lett 373(2):144–149PubMedCrossRefGoogle Scholar
  28. Schmechel DE, Saunders AM, Strittmatter WJ et al (1993) Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci USA 90(20):9649–9653PubMedCrossRefGoogle Scholar
  29. Sudweeks SN, Yakel JL (2000) Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons. J Physiol 527 Pt:3515–3552Google Scholar
  30. Weltzin MM, Schulte MK (2010) Pharmacological characterization of the allosteric modulator desformylflustrabromine and its interaction with alpha4beta2 neuronal nicotinic acetylcholine receptor orthosteric ligands. J Pharmacol Exp Ther 334(3):917–926PubMedCrossRefGoogle Scholar
  31. Whiting PJ, Schoepfer R, Swanson LW, Simmons DM, Lindstrom JM (1987) Functional acetylcholine receptor in PC12 cells reacts with a monoclonal antibody to brain nicotinic receptors. Nature 327(6122):515–518PubMedCrossRefGoogle Scholar
  32. Wu J, Kuo YP, George AA, Xu L, Hu J, Lukas RJ (2004) beta-Amyloid directly inhibits human alpha4beta2-nicotinic acetylcholine receptors heterologously expressed in human SH-EP1 cells. J Biol Chem 279(36):37842–37851PubMedCrossRefGoogle Scholar
  33. Yakel JL, Shao Z (2004) Functional and molecular characterization of neuronal nicotinic ACh receptors in rat hippocampal interneurons. Prog Brain Res 145:95–107PubMedCrossRefGoogle Scholar
  34. Young GT, Zwart R, Walker AS, Sher E, Millar NS (2008) Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proc Natl Acad Sci USA 105(38):14686–14691PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2011

Authors and Affiliations

  1. 1.Laboratory of Neurobiology, National Institute of Environmental Health SciencesNational Institutes of Health, Department of Health and Human ServicesResearch Triangle ParkUSA

Personalised recommendations