Skip to main content
SpringerLink
Log in

Targeting Brain α7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease: Rationale and Current Status

  • Leading Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (AChRs), particularly the α7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-β-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the α7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-d-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target α7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, α7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades—together with the corresponding abnormalities in all these properties—to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Dineley KT, Westerman M, Bui D, Bell K, Ashe KH, Sweatt JD. Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer’s disease. J Neurosci. 2001;21:4125–33.

    CAS  PubMed  Google Scholar 

  2. Liu Y, Yoo MJ, Savonenko A, Stirling W, Price DL, Borchelt DR, Mamounas L, Lyons WE, Blue ME, Lee MK. Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer’s disease. J Neurosci. 2008;28:13805–14.

    CAS  PubMed  Google Scholar 

  3. Oddo S, Caccamo A, Green KN, Liang K, Tran L, Chen Y, Leslie FM, LaFerla FM. Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease. Proc Natl Acad Sci USA. 2005;102:3046–51.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Oddo S, Caccamo A, Tseng B, Cheng D, Vasilevko V, Cribbs DH, LaFerla FM. Blocking Abeta42 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein70-interacting protein: a mechanistic link between Abeta and tau pathology. J Neurosci. 2008;28:12163–75.

    CAS  PubMed  Google Scholar 

  5. Karlin A. Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci. 2002;3:102–14.

    CAS  PubMed  Google Scholar 

  6. Karlin A. A touching picture of nicotinic binding. Neuron. 2004;41:841–2.

    CAS  PubMed  Google Scholar 

  7. Barrantes FJ. Modulation of nicotinic acetylcholine receptor function through the outer and middle rings of transmembrane domains. Curr Opin Drug Discov Dev. 2003;6:620–32.

    CAS  Google Scholar 

  8. Miledi R, Molinoff P, Potter LT. Isolation of the cholinergic receptor protein of Torpedo electric tissue. Nature. 1971;229:554–7.

    CAS  PubMed  Google Scholar 

  9. Balass M, Katchalski-Katzir E, Fuchs S. The alpha-bungarotoxin binding site on the nicotinic acetylcholine receptor: analysis using a phage-epitope library. Proc Natl Acad Sci USA. 1997;94:6054–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Changeux JP, Devillers-Thiery A, Galzi JL, Bertrand D. New mutants to explore nicotinic receptor functions. Trends Pharmacol Sci. 1992;13:299–301.

    CAS  PubMed  Google Scholar 

  11. Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol. 2005;346:967–89.

    CAS  PubMed  Google Scholar 

  12. Brejc K, van Dijk WJ, Smit AB, Sixma TK. The 2.7 Å structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor. Novartis. Found. Symp. 2002;245:22–9.

  13. Celie PH, van Rossum-Fikkert SE, van Dijk WJ, Brejc K, Smit AB, Sixma TK. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron. 2004;41:907–14.

    CAS  PubMed  Google Scholar 

  14. Unwin N. Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes. Q Rev Biophys. 2013;46:283–322.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Gotti C, Riganti L, Vailati S, Clementi F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr Pharm Des. 2006;12:407–28.

    CAS  PubMed  Google Scholar 

  16. Kawashima K, Fujii T, Moriwaki Y, Misawa H, Horiguchi K. Reconciling neuronally and nonneuronally derived acetylcholine in the regulation of immune function. Ann N Y Acad Sci. 2012;1261:7–17.

    CAS  PubMed  Google Scholar 

  17. Maus AD, Pereira EF, Karachunski PI, Horton RM, Navaneetham D, Macklin K, Cortes WS, Albuquerque EX, Conti-Fine BM. Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol. 1998;54:779–88.

    CAS  PubMed  Google Scholar 

  18. Cuevas J, Berg DK. Mammalian nicotinic receptors with alpha7 subunits that slowly desensitize and rapidly recover from alpha-bungarotoxin blockade. J Neurosci. 1998;18:10335–44.

    CAS  PubMed  Google Scholar 

  19. Fucile S, Palma E, Mileo AM, Miledi R, Eusebi F. Human neuronal threonine-for-leucine-248 alpha 7 mutant nicotinic acetylcholine receptors are highly Ca2+ permeable. Proc Natl Acad Sci USA. 2000;97:3643–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Alkondon M, Pereira EF, Barbosa CT, Albuquerque EX. Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices. J Pharmacol Exp Ther. 1997;283:1396–411.

    CAS  PubMed  Google Scholar 

  21. Alkondon M, Albuquerque EX. The nicotinic acetylcholine receptor subtypes and their function in the hippocampus and cerebral cortex. Prog Brain Res. 2004;145:109–20.

    CAS  PubMed  Google Scholar 

  22. Descarries L, Gisiger V, Steriade M. Diffuse transmission by acetylcholine in the CNS. Prog Neurobiol. 1997;53:603–25.

    CAS  PubMed  Google Scholar 

  23. Bakanidze G, Roinishvili M, Chkonia E, Kitzrow W, Richter S, Neumann K, Herzog MH, Brand A, Puls I. Association of the nicotinic receptor alpha7 subunit gene (CHRNA7) with schizophrenia and visual backward masking. Front Psychiatry. 2013;4:133.

    PubMed Central  PubMed  Google Scholar 

  24. Banerjee C, Nyengaard JR, Wevers A, de Vos RA, Jansen Steur EN, Lindstrom J, Pilz K, Nowacki S, Bloch W, Schroder H. Cellular expression of alpha7 nicotinic acetylcholine receptor protein in the temporal cortex in Alzheimer’s and Parkinson’s disease: a stereological approach. Neurobiol Dis. 2000;7:666–72.

    CAS  PubMed  Google Scholar 

  25. Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry. 2008;165:1040–7.

    PubMed Central  PubMed  Google Scholar 

  26. Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R, Iversen P, Bauman M, Perry E. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain. 2002;125:1483–95.

    CAS  PubMed  Google Scholar 

  27. Levin ED, Mead T, Rezvani AH, Rose JE, Gallivan C, Gross R. The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats. Physiol Behav. 2000;71:565–70.

    CAS  PubMed  Google Scholar 

  28. Palma E, Conti L, Roseti C, Limatola C. Novel approaches to study the involvement of alpha7-nAChR in human diseases. Curr Drug Targets. 2012;13:579–86.

    CAS  PubMed  Google Scholar 

  29. Wallace TL, Porter RH. Targeting the nicotinic alpha7 acetylcholine receptor to enhance cognition in disease. Biochem Pharmacol. 2011;82:891–903.

    CAS  PubMed  Google Scholar 

  30. Wang HY, Lee DH, D’Andrea MR, Peterson PA, Shank RP, Reitz AB. Beta-amyloid(1–42) binds to alpha7 nicotinic acetylcholine receptor with high affinity: implications for Alzheimer’s disease pathology. J Biol Chem. 2000;275:5626–32.

    CAS  PubMed  Google Scholar 

  31. Moser N, Mechawar N, Jones I, Gochberg-Sarver A, Orr-Urtreger A, Plomann M, Salas R, Molles B, Marubio L, Roth U, Maskos U, Winzer-Serhan U, Bourgeois JP, Le Sourd AM, De Biasi B, Schroder H, Lindstrom J, Maelicke A, Changeux JP, Wevers A. Evaluating the suitability of nicotinic acetylcholine receptor antibodies for standard immunodetection procedures. J Neurochem. 2007;102:479–92.

    CAS  PubMed  Google Scholar 

  32. Dineley KT. Beta-amyloid peptide–nicotinic acetylcholine receptor interaction: the two faces of health and disease. Front Biosci. 2007;12:5030–8.

    CAS  PubMed  Google Scholar 

  33. Oz M, Lorke DE, Yang KH, Petroianu G. On the interaction of beta-amyloid peptides and alpha7-nicotinic acetylcholine receptors in Alzheimer’s disease. Curr Alzheimer Res. 2013;10:618–30.

    CAS  PubMed  Google Scholar 

  34. Ni R, Marutle A, Nordberg A. Modulation of alpha7 nicotinic acetylcholine receptor and fibrillar amyloid-beta interactions in Alzheimer’s disease brain. J Alzheimers Dis. 2013;33:841–51.

    CAS  PubMed  Google Scholar 

  35. Hernandez CM, Dineley KT. Alpha7 nicotinic acetylcholine receptors in Alzheimer’s disease: neuroprotective, neurotrophic or both? Curr Drug Targets. 2012;13:613–22.

    CAS  PubMed  Google Scholar 

  36. Chrobak JJ, Hanin I, Schmechel DE, Walsh TJ. AF64A-induced working memory impairment: behavioral, neurochemical and histological correlates. Brain Res. 1988;463:107–17.

    CAS  PubMed  Google Scholar 

  37. Hasselmo ME, Wyble BP, Wallenstein GV. Encoding and retrieval of episodic memories: role of cholinergic and GABAergic modulation in the hippocampus. Hippocampus. 1996;6:693–708.

    CAS  PubMed  Google Scholar 

  38. Olson L, Nordberg A, von Holst H, Backman L, Ebendal T, Alafuzoff I, Amberla K, Hartvig P, Herlitz A, Lilja A. Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report). J Neural Transm Park Dis Dement Sect. 1992;4:79–95.

    CAS  PubMed  Google Scholar 

  39. Buckingham SD, Jones AK, Brown LA, Sattelle DB. Nicotinic acetylcholine receptor signalling: roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacol Rev. 2009;61:39–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. D’Andrea MR, Nagele RG. Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer’s disease pyramidal neurons. Curr Pharm Des. 2006;12:677–84.

    PubMed  Google Scholar 

  41. Wevers A, Monteggia L, Nowacki S, Bloch W, Schutz U, Lindstrom J, Pereira EF, Eisenberg H, Giacobini E, de Vos RA, Steur EN, Maelicke A, Albuquerque EX, Schroder H. Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer’s disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein. Eur J Neurosci. 1999;11:2551–65.

    CAS  PubMed  Google Scholar 

  42. Keller C, Kadir A, Forsberg A, Porras O, Nordberg A. Long-term effects of galantamine treatment on brain functional activities as measured by PET in Alzheimer’s disease patients. J Alzheimers Dis. 2011;24:109–23.

    CAS  PubMed  Google Scholar 

  43. Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope T, Francis PT. Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology. 2000;55:1460–7.

    CAS  PubMed  Google Scholar 

  44. Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ. Choline acetyltransferase activity and cognitive domain scores of Alzheimer’s patients. Neurobiol Aging. 2000;21:11–7.

    CAS  PubMed  Google Scholar 

  45. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry. 1999;66:137–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Kar S, Slowikowski SP, Westaway D, Mount HT. Interactions between beta-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci. 2004;29:427–41.

    PubMed Central  PubMed  Google Scholar 

  47. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Siemers E, Sethuraman G, Mohs R. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50.

    CAS  PubMed  Google Scholar 

  48. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:311–21.

    CAS  PubMed  Google Scholar 

  49. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Wirth M, Madison CM, Rabinovici GD, Oh H, Landau SM, Jagust WJ. Alzheimer’s disease neurodegenerative biomarkers are associated with decreased cognitive function but not beta-amyloid in cognitively normal older individuals. J Neurosci. 2013;33:5553–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925–31.

    CAS  PubMed  Google Scholar 

  52. Wicklund L, Leao RN, Stromberg AM, Mousavi M, Hovatta O, Nordberg A, Marutle A. Beta-amyloid 1–42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic neurons. PLoS One. 2010;5:e15600.

    PubMed Central  PubMed  Google Scholar 

  53. Giacobini E, Gold G. Alzheimer disease therapy: moving from amyloid-beta to tau. Nat Rev Neurol. 2013;9:677–86.

    CAS  PubMed  Google Scholar 

  54. Hu JP, Xie JW, Wang CY, Wang T, Wang X, Wang SL, Teng WP, Wang ZY. Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways. Brain Res Bull. 2011;85:194–200.

    CAS  PubMed  Google Scholar 

  55. Macdonald A, Briggs K, Poppe M, Higgins A, Velayudhan L, Lovestone S. A feasibility and tolerability study of lithium in Alzheimer’s disease. Int J Geriatr Psychiatry. 2008;23:704–11.

    PubMed  Google Scholar 

  56. Tariot PN, Schneider LS, Cummings J, Thomas RG, Raman R, Jakimovich LJ, Loy R, Bartocci B, Fleisher A, Ismail MS, Porsteinsson A, Weiner M, Jack CR Jr, Thal L, Aisen PS. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 2011;68:853–61.

    CAS  PubMed  Google Scholar 

  57. Wischik C, Staff R. Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of tau-aggregation inhibitor therapy. J Nutr Health Aging. 2009;13:367–9.

    CAS  PubMed  Google Scholar 

  58. Mullane K, Williams M. Alzheimer’s therapeutics: continued clinical failures question the validity of the amyloid hypothesis, but what lies beyond? Biochem Pharmacol. 2013;85:289–305.

    CAS  PubMed  Google Scholar 

  59. Jack CR Jr. Alzheimer disease: new concepts on its neurobiology and the clinical role imaging will play. Radiology. 2012;263:344–61.

    PubMed Central  PubMed  Google Scholar 

  60. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9.

    PubMed Central  PubMed  Google Scholar 

  61. Dubois B, Feldman HH, Jacova C, Cummings JL, DeKosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol. 2010;9:1118–27.

    PubMed  Google Scholar 

  62. Jack CR Jr, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH. Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:257–62.

    PubMed Central  PubMed  Google Scholar 

  63. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:263–9.

    PubMed Central  PubMed  Google Scholar 

  64. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR Jr, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92.

    PubMed Central  PubMed  Google Scholar 

  65. Nordberg A. Mechanisms behind the neuroprotective actions of cholinesterase inhibitors in Alzheimer disease. Alzheimer Dis Assoc Disord. 2006;20:S12–8.

    CAS  PubMed  Google Scholar 

  66. De Ferrari GV, Canales MA, Shin I, Weiner LM, Silman I, Inestrosa NC. A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation. Biochemistry. 2001;40:10447–57.

    PubMed  Google Scholar 

  67. Darreh-Shori T, Soininen H. Effects of cholinesterase inhibitors on the activities and protein levels of cholinesterases in the cerebrospinal fluid of patients with Alzheimer’s disease: a review of recent clinical studies. Curr Alzheimer Res. 2010;7:67–73.

    CAS  PubMed  Google Scholar 

  68. Darreh-Shori T, Almkvist O, Guan ZZ, Garlind A, Strandberg B, Svensson AL, Soreq H, Hellstrom-Lindahl E, Nordberg A. Sustained cholinesterase inhibition in AD patients receiving rivastigmine for 12 months. Neurology. 2002;59:563–72.

    CAS  PubMed  Google Scholar 

  69. Rosler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stahelin HB, Hartman R, Gharabawi M. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ. 1999;318:633–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Konrath EL, Passos CS, Klein-Junior LC, Henriques AT. Alkaloids as a source of potential anticholinesterase inhibitors for the treatment of Alzheimer’s disease. J Pharm Pharmacol. 2013;65:1701–25.

    CAS  PubMed  Google Scholar 

  71. Kadir A, Almkvist O, Wall A, Langstrom B, Nordberg A. PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer’s disease. Psychopharmacology (Berl). 2006;188:509–20.

    CAS  Google Scholar 

  72. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Grut M, Strandberg B, Ringheim A, Eriksson B, Blomquist G, Langstrom B, Nordberg A. PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiol Aging. 2008;29:1204–17.

    CAS  PubMed  Google Scholar 

  73. Guo B, Xu L, Wei Y, Liu C. Research advances of Huperzia serrata (Thunb.) Trev. Zhongguo Zhong Yao Za Zhi. 2009;34:2018–23.

    PubMed  Google Scholar 

  74. Ma X, Tan C, Zhu D, Gang DR, Xiao P. Huperzine A from Huperzia species: an ethnopharmacolgical review. J Ethnopharmacol. 2007;113:15–34.

    CAS  PubMed  Google Scholar 

  75. Zhang HY, Tang XC. Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci. 2006;27:619–25.

    CAS  PubMed  Google Scholar 

  76. Liang YQ, Tang XC. Comparative effects of huperzine A, donepezil and rivastigmine on cortical acetylcholine level and acetylcholinesterase activity in rats. Neurosci Lett. 2004;361:56–9.

    CAS  PubMed  Google Scholar 

  77. Xu SS, Cai ZY, Qu ZW, Yang RM, Cai YL, Wang GQ, Su XQ, Zhong XS, Cheng RY, Xu WA, Li JX, Feng B. Huperzine-A in capsules and tablets for treating patients with Alzheimer disease. Zhongguo Yao Li Xue Bao. 1999;20:486–90.

    CAS  PubMed  Google Scholar 

  78. Zhang Z, Wang X, Chen Q, Shu L, Wang J, Shan G. Clinical efficacy and safety of huperzine alpha in treatment of mild to moderate Alzheimer disease, a placebo-controlled, double-blind, randomized trial. Zhonghua Yi Xue Za Zhi. 2002;82:941–4.

    CAS  PubMed  Google Scholar 

  79. Rafii MS, Walsh S, Little JT, Behan K, Reynolds B, Ward C, Jin S, Thomas R, Aisen PS. A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology. 2011;76:1389–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Lleo A, Greenberg SM, Growdon JH. Current pharmacotherapy for Alzheimer’s disease. Annu Rev Med. 2006;57:513–33.

    CAS  PubMed  Google Scholar 

  81. Tariot PN, Federoff HJ. Current treatment for Alzheimer disease and future prospects. Alzheimer Dis Assoc Disord. 2003;17(Suppl 4):S105–13.

    CAS  PubMed  Google Scholar 

  82. Kem WR. The brain alpha7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer’s disease: studies with DMXBA (GTS-21). Behav Brain Res. 2000;113:169–81.

    CAS  PubMed  Google Scholar 

  83. Levin ED, McClernon FJ, Rezvani AH. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl). 2006;184:523–39.

    CAS  Google Scholar 

  84. Inestrosa NC, Godoy JA, Vargas JY, Arrazola MS, Rios JA, Carvajal FJ, Serrano FG, Farias GG. Nicotine prevents synaptic impairment induced by amyloid-beta oligomers through alpha7-nicotinic acetylcholine receptor activation. Neuromol Med. 2013;15:549–69.

    CAS  Google Scholar 

  85. Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiacovo MP, Yankner BA. REST and stress resistance in ageing and Alzheimer’s disease. Nature. 2014;507:448–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Young JW, Geyer MA. Evaluating the role of the alpha-7 nicotinic acetylcholine receptor in the pathophysiology and treatment of schizophrenia. Biochem Pharmacol. 2013;86:1122–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Christopoulos A, Changeux JP, Catterall WA, Fabbro D, Burris TP, Cidlowski JA, Olsen RW, Peters JA, Neubig RR, Pin JP, Sexton PM, Kenakin TP, Ehlert FJ, Spedding M, Langmead CJ. International Union of Basic and Clinical Pharmacology. XC. Multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands. Pharmacol Rev. 2014;66:918–47.

    PubMed  Google Scholar 

  88. Picciotto MR, Addy NA, Mineur YS, Brunzell DH. It is not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol. 2008;84:329–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Werkheiser JL, Sydserff S, Hubbs SJ, Ding M, Eisman MS, Perry D, Williams AJ, Smith JS, Mrzljak L, Maier DL. Ultra-low exposure to alpha-7 nicotinic acetylcholine receptor partial agonists elicits an improvement in cognition that corresponds with an increase in alpha-7 receptor expression in rodents: implications for low dose clinical efficacy. Neuroscience. 2011;186:76–87.

    CAS  PubMed  Google Scholar 

  90. Brody AL, Mukhin AG, Stephanie S, Mamoun MS, Kozman M, Phuong J, Neary M, Luu T, Mandelkern MA. Treatment for tobacco dependence: effect on brain nicotinic acetylcholine receptor density. Neuropsychopharmacology. 2013;38:1548–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Ridley DL, Rogers A, Wonnacott S. Differential effects of chronic drug treatment on alpha3* and alpha7 nicotinic receptor binding sites, in hippocampal neurones and SH-SY5Y cells. Br J Pharmacol. 2001;133:1286–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Medeiros R, Castello NA, Cheng D, Kitazawa M, Baglietto-Vargas D, Green KN, Esbenshade TA, Bitner RS, Decker MW, LaFerla FM. alpha7 nicotinic receptor agonist enhances cognition in aged 3xTg-AD mice with robust plaques and tangles. Am J Pathol. 2014;184:520–9.

    CAS  PubMed  Google Scholar 

  93. Kroker KS, Moreth J, Kussmaul L, Rast G, Rosenbrock H. Restoring long-term potentiation impaired by amyloid-beta oligomers: comparison of an acetylcholinesterase inhibitor and selective neuronal nicotinic receptor agonists. Brain Res Bull. 2013;96:28–38.

    CAS  PubMed  Google Scholar 

  94. Prickaerts J, van Goethem NP, Chesworth R, Shapiro G, Boess FG, Methfessel C, Reneerkens OA, Flood DG, Hilt D, Gawryl M, Bertrand S, Bertrand D, Konig G. EVP-6124, a novel and selective alpha7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of alpha7 nicotinic acetylcholine receptors. Neuropharmacology. 2012;62:1099–110.

    CAS  PubMed  Google Scholar 

  95. Mazurov AA, Kombo DC, Hauser TA, Miao L, Dull G, Genus JF, Fedorov NB, Benson L, Sidach S, Xiao Y, Hammond PS, James JW, Miller CH, Yohannes D. Discovery of (2S,3R)-N-[2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (TC-5619), a selective alpha7 nicotinic acetylcholine receptor agonist, for the treatment of cognitive disorders. J Med Chem. 2012;55:9793–809.

    CAS  PubMed  Google Scholar 

  96. Briggs CA, Anderson DJ, Brioni JD, Buccafusco JJ, Buckley MJ, Campbell JE, Decker MW, Donnelly-Roberts D, Elliott RL, Gopalakrishnan M, Holladay MW, Hui YH, Jackson WJ, Kim DJ, Marsh KC, O’Neill A, Prendergast MA, Ryther KB, Sullivan JP, Arneric SP. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav. 1997;57:231–41.

    CAS  PubMed  Google Scholar 

  97. Palma E, Bertrand S, Binzoni T, Bertrand D. Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine. J Physiol. 1996;491(Pt 1):151–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Callahan PM, Hutchings EJ, Kille NJ, Chapman JM, Terry AV Jr. Positive allosteric modulator of alpha7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Neuropharmacology. 2013;67:201–12.

    CAS  PubMed  Google Scholar 

  99. Dinklo T, Shaban H, Thuring JW, Lavreysen H, Stevens KE, Zheng L, Mackie C, Grantham C, Vandenberk I, Meulders G, Peeters L, Verachtert H, De PE, Lesage AS. Characterization of 2-[[4-fluoro-3-(trifluoromethyl)phenyl]amino]-4-(4-pyridinyl)-5-thiazolemethanol (JNJ-1930942), a novel positive allosteric modulator of the {alpha}7 nicotinic acetylcholine receptor. J Pharmacol Exp Ther. 2011;336:560–74.

    CAS  PubMed  Google Scholar 

  100. Arias HR, Gu RX, Feuerbach D, Guo BB, Ye Y, Wei DQ. Novel positive allosteric modulators of the human alpha7 nicotinic acetylcholine receptor. Biochemistry. 2011;50:5263–78.

    CAS  PubMed  Google Scholar 

  101. Dunlop J, Lock T, Jow B, Sitzia F, Grauer S, Jow F, Kramer A, Bowlby MR, Randall A, Kowal D, Gilbert A, Comery TA, Larocque J, Soloveva V, Brown J, Roncarati R. Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b’]di pyrrole-1(2H)-carboxamide). J Pharmacol Exp Ther. 2009;328:766–76.

    CAS  PubMed  Google Scholar 

  102. Gopalakrishnan SM, Philip BM, Gronlien JH, Malysz J, Anderson DJ, Gopalakrishnan M, Warrior U, Burns DJ. Functional characterization and high-throughput screening of positive allosteric modulators of alpha7 nicotinic acetylcholine receptors in IMR-32 neuroblastoma cells. Assay Drug Dev Technol. 2011;9:635–45.

    CAS  PubMed  Google Scholar 

  103. Malysz J, Gronlien JH, Anderson DJ, Hakerud M, Thorin-Hagene K, Ween H, Wetterstrand C, Briggs CA, Faghih R, Bunnelle WH, Gopalakrishnan M. In vitro pharmacological characterization of a novel allosteric modulator of alpha 7 neuronal acetylcholine receptor, 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744), exhibiting unique pharmacological profile. J Pharmacol Exp Ther. 2009;330:257–67.

    CAS  PubMed  Google Scholar 

  104. Ng HJ, Whittemore ER, Tran MB, Hogenkamp DJ, Broide RS, Johnstone TB, Zheng L, Stevens KE, Gee KW. Nootropic alpha7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc Natl Acad Sci USA. 2007;104:8059–64.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Timmermann DB, Gronlien JH, Kohlhaas KL, Nielsen EO, Dam E, Jorgensen TD, Ahring PK, Peters D, Holst D, Christensen JK, Malysz J, Briggs CA, Gopalakrishnan M, Olsen GM. An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J Pharmacol Exp Ther. 2007;323:294–307.

    CAS  PubMed  Google Scholar 

  106. Williams DK, Wang J, Papke RL. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations. Biochem Pharmacol. 2011;82:915–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Gronlien JH, Hakerud M, Ween H, Thorin-Hagene K, Briggs CA, Gopalakrishnan M, Malysz J. Distinct profiles of alpha7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes. Mol Pharmacol. 2007;72:715–24.

    PubMed  Google Scholar 

  108. Gill JK, Savolainen M, Young GT, Zwart R, Sher E, Millar NS. Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proc Natl Acad Sci USA. 2011;108:5867–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Hurst RS, Hajos M, Raggenbass M, Wall TM, Higdon NR, Lawson JA, Rutherford-Root KL, Berkenpas MB, Hoffmann WE, Piotrowski DW, Groppi VE, Allaman G, Ogier R, Bertrand S, Bertrand D, Arneric SP. A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. J Neurosci. 2005;25:4396–405.

    CAS  PubMed  Google Scholar 

  110. Arredondo J, Chernyavsky AI, Grando SA. SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes. Life Sci. 2007;80:2243–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Fujii T, Horiguchi K, Sunaga H, Moriwaki Y, Misawa H, Kasahara T, Tsuji S, Kawashima K. SLURP-1, an endogenous alpha7 nicotinic acetylcholine receptor allosteric ligand, is expressed in CD205(+) dendritic cells in human tonsils and potentiates lymphocytic cholinergic activity. J Neuroimmunol. 2014;267:43–9.

    CAS  PubMed  Google Scholar 

  112. Moriwaki Y, Yoshikawa K, Fukuda H, Fujii YX, Misawa H, Kawashima K. Immune system expression of SLURP-1 and SLURP-2, two endogenous nicotinic acetylcholine receptor ligands. Life Sci. 2007;80:2365–8.

    CAS  PubMed  Google Scholar 

  113. Moriwaki Y, Watanabe Y, Shinagawa T, Kai M, Miyazawa M, Okuda T, Kawashima K, Yabashi A, Waguri S, Misawa H. Primary sensory neuronal expression of SLURP-1, an endogenous nicotinic acetylcholine receptor ligand. Neurosci Res. 2009;64:403–12.

    CAS  PubMed  Google Scholar 

  114. Livingstone PD, Dickinson JA, Srinivasan J, Kew JN, Wonnacott S. Glutamate-dopamine crosstalk in the rat prefrontal cortex is modulated by alpha7 nicotinic receptors and potentiated by PNU-120596. J Mol Neurosci. 2010;40:172–6.

    CAS  PubMed  Google Scholar 

  115. Thomsen MS, El-Sayed M, Mikkelsen JD. Differential immediate and sustained memory enhancing effects of alpha7 nicotinic receptor agonists and allosteric modulators in rats. PLoS One. 2011;6:e27014.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Lopes C, Pereira EF, Wu HQ, Purushottamachar P, Njar V, Schwarcz R, Albuquerque EX. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors. J Pharmacol Exp Ther. 2007;322:48–58.

    CAS  PubMed  Google Scholar 

  117. Woodruff-Pak DS, Lander C, Geerts H. Nicotinic cholinergic modulation: galantamine as a prototype. CNS Drug Rev. 2002;8:405–26.

    CAS  PubMed  Google Scholar 

  118. Moriguchi S, Marszalec W, Zhao X, Yeh JZ, Narahashi T. Mechanism of action of galantamine on N-methyl-d-aspartate receptors in rat cortical neurons. J Pharmacol Exp Ther. 2004;310:933–42.

    CAS  PubMed  Google Scholar 

  119. Samochocki M, Hoffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lubbert H, Albuquerque EX, Maelicke A. Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther. 2003;305:1024–36.

    CAS  PubMed  Google Scholar 

  120. Hansen SB, Taylor P. Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors. J Mol Biol. 2007;369:895–901.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Zwart R, De FG, Broad LM, McPhie GI, Pearson KH, Baldwinson T, Sher E. 5-Hydroxyindole potentiates human alpha 7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices. Neuropharmacology. 2002;43:374–84.

    CAS  PubMed  Google Scholar 

  122. van Hooft JA, van der Haar E, Vijverberg HP. Allosteric potentiation of the 5-HT3 receptor-mediated ion current in N1E-115 neuroblastoma cells by 5-hydroxyindole and analogues. Neuropharmacology. 1997;36:649–53.

    PubMed  Google Scholar 

  123. Grilli M, Raiteri L, Patti L, Parodi M, Robino F, Raiteri M, Marchi M. Modulation of the function of presynaptic alpha7 and non-alpha7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain. Br J Pharmacol. 2006;149:724–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Patti L, Raiteri L, Grilli M, Parodi M, Raiteri M, Marchi M. P2X(7) receptors exert a permissive role on the activation of release-enhancing presynaptic alpha7 nicotinic receptors co-existing on rat neocortex glutamatergic terminals. Neuropharmacology. 2006;50:705–13.

    CAS  PubMed  Google Scholar 

  125. Kooyman AR, van Hooft JA, Vijverberg HP. 5-Hydroxyindole slows desensitization of the 5-HT3 receptor-mediated ion current in N1E-115 neuroblastoma cells. Br J Pharmacol. 1993;108:287–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Broad LM, Zwart R, Pearson KH, Lee M, Wallace L, McPhie GI, Emkey R, Hollinshead SP, Dell CP, Baker SR, Sher E. Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators. J Pharmacol Exp Ther. 2006;318:1108–17.

    CAS  PubMed  Google Scholar 

  127. Akiyama T, Ishida J, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fukami Y. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987;262:5592–5.

    CAS  PubMed  Google Scholar 

  128. Charpantier E, Wiesner A, Huh KH, Ogier R, Hoda JC, Allaman G, Raggenbass M, Feuerbach D, Bertrand D, Fuhrer C. Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and Src-family kinases. J Neurosci. 2005;25:9836–49.

    CAS  PubMed  Google Scholar 

  129. Cho CH, Song W, Leitzell K, Teo E, Meleth AD, Quick MW, Lester RA. Rapid upregulation of alpha7 nicotinic acetylcholine receptors by tyrosine dephosphorylation. J Neurosci. 2005;25:3712–23.

    CAS  PubMed  Google Scholar 

  130. Blake RA, Broome MA, Liu X, Wu J, Gishizky M, Sun L, Courtneidge SA. SU6656, a selective src family kinase inhibitor, used to probe growth factor signaling. Mol Cell Biol. 2000;20:9018–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Zakar T, Mijovic JE, Bhardwaj D, Olson DM. Tyrosine kinase inhibitors block the glucocorticoid stimulation of prostaglandin endoperoxide H synthase expression in amnion cells. Can J Physiol Pharmacol. 1999;77:138–42.

    CAS  PubMed  Google Scholar 

  132. Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007;47:699–729.

    CAS  PubMed  Google Scholar 

  133. Krause RM, Buisson B, Bertrand S, Corringer PJ, Galzi JL, Changeux JP, Bertrand D. Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor. Mol Pharmacol. 1998;53:283–94.

    CAS  PubMed  Google Scholar 

  134. Khakh BS, Proctor WR, Dunwiddie TV, Labarca C, Lester HA. Allosteric control of gating and kinetics at P2X(4) receptor channels. J Neurosci. 1999;19:7289–99.

    CAS  PubMed  Google Scholar 

  135. Sattelle DB, Buckingham SD, Akamatsu M, Matsuda K, Pienaar IS, Jones AK, Sattelle BM, Almond A, Blundell CD. Comparative pharmacology and computational modelling yield insights into allosteric modulation of human alpha7 nicotinic acetylcholine receptors. Biochem Pharmacol. 2009;78:836–43.

    CAS  PubMed  Google Scholar 

  136. Shan Q, Haddrill JL, Lynch JW. Ivermectin, an unconventional agonist of the glycine receptor chloride channel. J Biol Chem. 2001;276:12556–64.

    CAS  PubMed  Google Scholar 

  137. Sigel E, Baur R. Effect of avermectin B1a on chick neuronal gamma-aminobutyrate receptor channels expressed in Xenopus oocytes. Mol Pharmacol. 1987;32:749–52.

    CAS  PubMed  Google Scholar 

  138. Grishin AA, Kolesik P, Coles C, Kolev Y, Wagner S, Huyard B, Andriambeloson E, Harvey A, O’Connor SM. BNC375, a novel positive allosteric modulator of the a7 nicotinic acetylcholine receptor, exhibits cognitive enhancement in rodent behavioural models. 2013. p. 143.

  139. Friis S, Mathes C, Sunesen M, Bowlby MR, Dunlop J. Characterization of compounds on nicotinic acetylcholine receptor alpha7 channels using higher throughput electrophysiology. J Neurosci Methods. 2009;177:142–8.

    CAS  PubMed  Google Scholar 

  140. Wallace TL, Rocha SM, Yeo H, Sahdeo S, Tehim A, Santarelli L. Cognitive enhancing properties of positive allosteric modulators of the nicotinic a7 receptor. Biochem Pharmacol. 2007;74(8).

  141. McLean SL, Idris NF, Grayson B, Gendle DF, Mackie C, Lesage AS, Pemberton DJ, Neill JC. PNU-120596, a positive allosteric modulator of alpha7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats. J Psychopharmacol. 2012;26:1265–70.

    CAS  PubMed  Google Scholar 

  142. Faghih R, Gopalakrishnan SM, Gronlien JH, Malysz J, Briggs CA, Wetterstrand C, Ween H, Curtis MP, Sarris KA, Gfesser GA, El-Kouhen R, Robb HM, Radek RJ, Marsh KC, Bunnelle WH, Gopalakrishnan M. Discovery of 4-(5-(4-chlorophenyl)-2-methyl-3-propionyl-1H-pyrrol-1-yl)benzenesulfonamide (A-867744) as a novel positive allosteric modulator of the alpha7 nicotinic acetylcholine receptor. J Med Chem. 2009;52:3377–84.

    CAS  PubMed  Google Scholar 

  143. Dickinson JA, Kew JN, Wonnacott S. Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms. Mol Pharmacol. 2008;74:348–59.

    CAS  PubMed  Google Scholar 

  144. El KR, Hu M, Anderson DJ, Li J, Gopalakrishnan M. Pharmacology of alpha7 nicotinic acetylcholine receptor mediated extracellular signal-regulated kinase signalling in PC12 cells. Br J Pharmacol. 2009;156:638–48.

    Google Scholar 

  145. Steiner RC, Heath CJ, Picciotto MR. Nicotine-induced phosphorylation of ERK in mouse primary cortical neurons: evidence for involvement of glutamatergic signaling and CaMKII. J Neurochem. 2007;103:666–78.

    CAS  PubMed  Google Scholar 

  146. Bitner RS, Bunnelle WH, Anderson DJ, Briggs CA, Buccafusco J, Curzon P, Decker MW, Frost JM, Gronlien JH, Gubbins E, Li J, Malysz J, Markosyan S, Marsh K, Meyer MD, Nikkel AL, Radek RJ, Robb HM, Timmermann D, Sullivan JP, Gopalakrishnan M. Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. J Neurosci. 2007;27:10578–87.

    CAS  PubMed  Google Scholar 

  147. Kennett GA, Wood MD, Bright F, Cilia J, Piper DC, Gager T, Thomas D, Baxter GS, Forbes IT, Ham P, Blackburn TP. In vitro and in vivo profile of SB 206553, a potent 5-HT2C/5-HT2B receptor antagonist with anxiolytic-like properties. Br J Pharmacol. 1996;117:427–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Moriguchi S, Shioda N, Yamamoto Y, Tagashira H, Fukunaga K. The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices. J Neurochem. 2012;121:44–53.

    CAS  PubMed  Google Scholar 

  149. Yamaguchi Y, Takeda K, Hino M. Combination effects of ZSET1446/ST101 with memantine on cognitive function and extracellular acetylcholine in the hippocampus. J Pharmacol Sci. 2013;123:347–55.

  150. Yamamoto Y, Shioda N, Han F, Moriguchi S, Fukunaga K. Novel cognitive enhancer ST101 enhances acetylcholine release in mouse dorsal hippocampus through T-type voltage-gated calcium channel stimulation. J Pharmacol Sci. 2013;121:212–26.

    CAS  PubMed  Google Scholar 

  151. Yang Y, Paspalas CD, Jin LE, Picciotto MR, Arnsten AF, Wang M. Nicotinic alpha7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proc Natl Acad Sci USA. 2013;110:12078–83.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

Drs. Vallés, Borroni, and Barrantes declare no conflicts of interest. Resources employed during the preparation of this review were provided by Grants PICT 2011-0604 from FONCYT, Ministry of Science and Technology and PIP No. 112-201101-01023 from the National Scientific and Technical Research Council of Argentina (CONICET) to F.J.B.

Author information

Author notes

  1. María Virginia Borroni

    Present address: Planta Piloto de Ingeniería Química (PLAPIQUI), CONICET, B8000FWB, Bahía Blanca, Argentina

Authors and Affiliations

  1. Instituto de Investigaciones Bioquímicas de Bahía Blanca, B8000FWB, Bahía Blanca, Argentina

    Ana Sofía Vallés & María Virginia Borroni

  2. Laboratory of Molecular Neurobiology, Faculty of Medical Sciences, Institute for Biomedical Research, UCA-CONICET, Av. Alicia Moreau de Justo 1600, C1107AFF, Buenos Aires, Argentina

    Francisco J. Barrantes

Authors
  1. Ana Sofía Vallés
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. María Virginia Borroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francisco J. Barrantes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Francisco J. Barrantes.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vallés, A.S., Borroni, M.V. & Barrantes, F.J. Targeting Brain α7 Nicotinic Acetylcholine Receptors in Alzheimer’s Disease: Rationale and Current Status. CNS Drugs 28, 975–987 (2014). https://doi.org/10.1007/s40263-014-0201-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-014-0201-3

Keywords

Search

Navigation