M1 Muscarinic Agonists: A Comprehensive Therapy Against Major Hallmarks of Alzheimer's Disease

  • Abraham Fisher

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized, inter alia, by memory and cognitive loss, synaptic loss, amyloid plaques containing the β-amyloid (Aβ) peptide, degeneration of cholinergic neurons that ascend from the basal forebrain to cortical and hippocampal areas, and neurofibrillary tangles (NFT) (review: Blennow, deLeon, & Zetterberg, 2002).


Tg2576 Mouse Muscarinic Agonist Comprehensive Therapy Major Hallmark Chronic Nicotine Treatment 


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  1. Anagnostaras, S. G., Murphy, G. G., Hamilton, S. E., Mitchell, S. L., Rahnama, N. P., Nathanson, N. M., et al. (2003). Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nature Neuroscience, 6, 51–58.CrossRefPubMedGoogle Scholar
  2. Auld, D. S., Kornecook, T. J., Bastianetto, S., & Quirion, R. (2002). Alzheimer's disease and the basal forebrain cholinergic system: Relations to beta-amyloid peptides, cognition, and treatment strategies. Progress in Neurobiology, 68, 209–245.CrossRefPubMedGoogle Scholar
  3. Balaraman, Y., Limaye, A. R., Levey, A. I., & Srinivasan, S. (2006). Glycogen synthase kinase 3beta and Alzheimer's disease: Pathophysiological and therapeutic significance. Cellular and Molecular Life Sciences, 63, 1226–1235.CrossRefPubMedGoogle Scholar
  4. Bartolomeo, A. C., Morris, H., Buccafusco, J. J., Kille N., Rosenzweig-Lipson, S., Husbands, M. G., et al. (2000). The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist. The Journal of Pharmacology and Experimental Therapeutics, 292, 584–596.PubMedGoogle Scholar
  5. Beach, T. G. (2002). Muscarinic agonists as preventative therapy for Alzheimer's disease. Current Opinion in Investigational Drugs, 3, 1633–1636.PubMedGoogle Scholar
  6. Beach, T. G., Walker, D. G., Sue, L. I., Scott, S., Layne, K. J., Newell, A. J., et al. (2003). Immunotoxin lesion of the cholinergic nucleus basalis causes Aβ deposition: Towards a physiologic animal model of Alzheimer's disease. Current Medicinal Chemistry–Immunology, Endocrine & Metabolic Agents, 3, 233–243.Google Scholar
  7. Beach, T. G., Walker, D. G., Potter, P. E., Sue, L. I., & Fisher, A. (2001). Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists. Brain Research, 905, 220–223.CrossRefPubMedGoogle Scholar
  8. Birks, J. (2006). Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database of Systematic Reviews, 25, CD005593.Google Scholar
  9. Blennow, K., deLeon, M. J., & Zetterberg, H. (2006). Alzheimer's disease. Lancet, 368, 387–403.CrossRefPubMedGoogle Scholar
  10. Bodick, N. C., Offen, W. W., Levey, A. I., Cutler, N. R., Gauthier, S. G., Satlin, A., et al. (1997). Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Archives of Neurology, 54, 465–473.PubMedGoogle Scholar
  11. Bons, N., Rieger, F., Prudhomme, D., Fisher, A., & Krause, K. H. (2005). Microcebus murinus: A useful primate model for human cerebral aging and Alzheimer's disease? Genes, Brain, and Behavior, 5, 120–130.CrossRefGoogle Scholar
  12. Bullock, R. (2006). Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: The evidence to date. Alzheimer Disease and Associated Disorders, 20, 23–29.CrossRefPubMedGoogle Scholar
  13. Bymaster, F. P., Whitesitt, C. A., Shannon, H. E., DeLapp, N., Ward, J. S., Calligaro, D. O., et al. (1997). Xanomeline: A selective muscarinic agonist for the treatment of Alzheimer's disease. Drug Development and Research, 40, 158–170.CrossRefGoogle Scholar
  14. Caccamo, A., Oddo, S., Billings, L. M., Green, K. N., Martinez-Coria, H., Fisher, A., et al. (2006). M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron, 49, 671–682.CrossRefPubMedGoogle Scholar
  15. Capsoni, S., Giannotta, S., Stebel, M., Garcia, A. A., De Rosa, R., Villetti, G., et al. (2004). Ganstigmine and donepezil improve neurodegeneration in AD11 antinerve growth factor transgenic mice. American Journal of Alzheimer's Disease and Other Dementias, 19, 153–160.CrossRefPubMedGoogle Scholar
  16. De Ferrari, G. V., & Inestrosa, N. C. (2000). Wnt signaling function in Alzheimer's disease. Brain Research Reviews, 33, 1–12.CrossRefPubMedGoogle Scholar
  17. Dong, H., Csernansky, C. A., Martin, M. V., Bertchume, A., Vallera, D., & Csernansky, J. G. (2005). Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer's disease. Psychopharmacology (Berlin), 181, 145–152.CrossRefGoogle Scholar
  18. Etcheberrigaray, R., Tan, M., Dewachter, I., Cuiperi, C., van der Auwera, I., Wera, S., et al. (2004). Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 101, 11141–11146.CrossRefPubMedGoogle Scholar
  19. Ensinger, H. A., Bechtel, W. D., Birke, F. W., Mendla, K. L., Mierau, J., Speck, G., et al. (1997). WAL 2014 FU (Talsaclidine): A preferentially neuron activating muscarinic agonist for the treatment of Alzheimer's disease. Drug Development Research, 40, 144–157.CrossRefGoogle Scholar
  20. Fisher, A. (1997). Muscarinic agonists for the treatment of Alzheimer's disease: Progress and perspectives. Expert Opinion on Investigational Drugs, 6, 1395–1411.CrossRefPubMedGoogle Scholar
  21. Fisher A. (2000). Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists. Japanese Journal of Pharmacology, 84, 101–112.CrossRefPubMedGoogle Scholar
  22. Fisher, A. (2005). Muscarinic agonists and antagonists–some therapeutic applications. In: E. Giacobini, & G. Pepeu (Eds.), The brain cholinergic system in health and disease (pp. 169–180). U.K.: Informa Healthcare, Taylor & Francis. London.Google Scholar
  23. Fisher, A., Brandeis, R., Bar-Ner, N., Kliger-Spatz, M., Natan, N., Sonego, H., et al. (2002). AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease. Journal of Molecular Neuroscience, 19, 145–153.CrossRefPubMedGoogle Scholar
  24. Fisher, A., Brandeis, R., Haring, R., Bar-Ner, N., Kliger-Spatz, M., Natan, N., et al. (2002). Impact of muscarinic agonists for successful therapy of Alzheimer's disease. Journal of Neural Transmission. Supplementum, 62, 189–202.PubMedGoogle Scholar
  25. Fisher, A., Brandeis, R., Haring, R., Eshhar, N., Heldman, E., Karton Y., et al. (1998). Novel m1 muscarinic agonists in treatment and delaying the progression of Alzheimer's disease: A unifying hypothesis. Journal of Physiology, Paris, 92, 337–340.CrossRefPubMedGoogle Scholar
  26. Fisher, A., Kealler, E., & Bons, N. (2000). Cognitive and behavioral improvements in the aged primate Microcebus murinus following one year treatment with the M1 muscarinic agonist, AF150(S). World Conference on AD: Washington DC, July 9–13.Google Scholar
  27. Farias, G. G., Godoy, J. A., Hernandez, F., Avila, J., Fisher, A., & Inestrosa, N. C. (2004). M1 muscarinic receptor activation protects neurons from beta-amyloid toxicity. A role for Wnt signaling pathway. Neurobiology of Disease, 17, 337–348.CrossRefPubMedGoogle Scholar
  28. Forlenza, O. V., Spink, J. M., Dayanandan, R., Anderton, B. H., Olesen, O. F., & Lovestone, S. (2000). Muscarinic agonists reduce τ phosphorylation in non-neuronal cells via GSK-3β inhibition and in neurons. Journal of Neural Transmission, 107, 1201–1212.CrossRefPubMedGoogle Scholar
  29. Genis, I., Fisher, A., & Michaelson, D. M. (1999). Site-specific dephosphorylation of tau in apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment. Journal of Neurochemistry, 12, 206–213.CrossRefGoogle Scholar
  30. Grimes, C. A., & Jope, R. S. (2001). The multifaceted roles of glycogen synthase kinase-3β in cellular signaling. Progress in Neurobiology, 65, 391–426.CrossRefPubMedGoogle Scholar
  31. Guo, T., & Hobbs, D. W. (2006). Development of BACE1 inhibitors for Alzheimer's disease. Current Medicinal Chemistry, 13, 1811–1829.CrossRefPubMedGoogle Scholar
  32. Haring, R., Fisher, A., Marciano, D., Pittel, Z., Kloog, Y., Zuckerman, A., et al. (1998). Mitogen-activated protein kinase-dependent and protein kinase C-dependent pathways link the M1 muscarinic receptor to amyloid precursor protein secretion. Journal of Neurochemistry, 71, 2094–2103.PubMedGoogle Scholar
  33. Hellstrom-Lindahl, E., Moore, H., & Nordberg, A. (2000). Increased levels of τ protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists, Journal of Neurochemistry, 74, 777–784.CrossRefPubMedGoogle Scholar
  34. Hellstrom-Lindhal, E., Court, J., Keverene, J., Svedberg, M., Lee, M., Marutle, A., et al. (2004). Nicotine reduces A beta in the brain and cerebral vessels of APPsw mice. The European Journal of Neuroscience, 19, 2703–2710.CrossRefGoogle Scholar
  35. Hock, C, Madallena, A, Raschig, A, Muller-Spahn, F., Eschweiller, G., Hager, I., et al. (2003). Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of Abeta42 in patients with Alzheimer's disease. Amyloid, 10, 1–6.PubMedGoogle Scholar
  36. Kar, S., Slowikowski S. P., Westaway, D., & Mount, H. T. (2004). Interactions between beta-amyloid and central cholinergic neurons: Implications for Alzheimer's disease. Journal of Psychiatry and Neuroscience, 29, 427–441.PubMedGoogle Scholar
  37. Kurumatani, T., Fastbom, J., Bonkale, W. L., Bogdanovic, N., Winblad, B., Ohn, T. G., et al. (1998). Loss of inositol 1, 4, 5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer's disease neurofibrillary pathology. Brain Research, 796, 209–221.CrossRefPubMedGoogle Scholar
  38. Levey, A. I. (1996). Muscarinic acetylcholine receptor expression in memory circuits: Implications for treatment of Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America, 93, 13541–13546.CrossRefPubMedGoogle Scholar
  39. Liskowsky, W., & Schliebs, R. (2006). Muscarinic acetylcholine receptor inhibition in transgenic Alzheimer-like Tg2576 mice by scopolamine favours the amyloidogenic route of processing of amyloid precursor protein. International Journal of Developmental Neuroscience, 24, 149–156.CrossRefPubMedGoogle Scholar
  40. Meier, E., Frederiksen K., Nielsen, M., Lembol, H. L., Pedersen, H., & Hyttel, J. (1997). Pharmacological in vitro characterization of the arecoline bioisostere, Lu 25–109-T, a muscarinic compound with M1-agonistic and M2/M3-antagonistic properties. Drug Development Research, 40, 1–16.CrossRefGoogle Scholar
  41. Mudher, A., & Lovestone, S. (2002). Alzheimer's disease-do tauists and baptists finally shake hands? Trends in Neurosciences, 25, 22–26.CrossRefPubMedGoogle Scholar
  42. Muller, D. M., Mendla, K., Farber, S. A., & Nitsch, R. M. (1997). Muscarinic M1 receptor agonists increase the secretion of the amyloid precursor protein ectodomain. Life Sciences, 60, 985–991.CrossRefPubMedGoogle Scholar
  43. Mulugeta, E., Karlsson, E., Islam, A., Kalaria, R., Mangat, H., Winblad, B., et al. (2003). Loss of muscarinic M(4) receptors in hippocampus of Alzheimer patients. Brain Research, 960, 259–262.CrossRefPubMedGoogle Scholar
  44. Nitsch, R. M., Slack, B. E., Wurtman, R. J., & Growdon, J. H. (1992). Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science, 58, 304–307.CrossRefGoogle Scholar
  45. Nitsch, R. M., Deng, M., Tennis, M., Schoenfield, D., & Growdon, J. H. (2000). The selective muscarinic M1 agonist AF102B decreases levels of total A (beta) in cerebrospinal fluid of patients with Alzheimer's disease. Annals of Neurology, 48, 913–918.CrossRefPubMedGoogle Scholar
  46. Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., et al. (2003). Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron, 39, 409–421.CrossRefPubMedGoogle Scholar
  47. Oddo, S., Caccamo, A., Green, K. N., Liang, K, Tran, L., Chen, Y., et al. (2005). Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America, 102, 3046–3051.CrossRefPubMedGoogle Scholar
  48. Parnetti, L., Amici, S., Lanar, A., Romani, C., Antognelli, C., Andreasen, N., et al. (2002). Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in Alzheimer's disease patients before and after treatment with different AChE inhibitors. Neurological Sciences, 23 (Suppl. 2), s95–s96.CrossRefPubMedGoogle Scholar
  49. Perry, E. K., Kilford, L., Lees, A. J., Burn, D. J., & Perry, R. H. (2003). Increased Alzheimer pathology in Parrkinson's disease is associated with antimuscarinic drugs. Annals of Neurology, 54, 235–238.CrossRefPubMedGoogle Scholar
  50. Pittel, Z., Heldman, E., Barg, J., Haring, R., & Fisher, A. (1996). Muscarinic control of amyloid precursor protein secretion in rat cerebral cortex and cerebellum. Brain Research, 742, 299–304.CrossRefPubMedGoogle Scholar
  51. Planel, E., Sun, X., & Takashima A. (2002). Role of GSK-3b in Alzheimer's disease pathology. Drug Development Research, 56, 491–510.CrossRefGoogle Scholar
  52. Racchi, M., Mazzucchelli, M., Porrello, E., Lanni, C., & Govoni, S. (2004). Acetylcholinesterase inhibitors: Novel activities of old molecules. Pharmacological Research, 50, 441–451.CrossRefPubMedGoogle Scholar
  53. Ringman, J. M., & Cummings, J. L. (2006). Current and emerging pharmacological treatment options for dementia. Behavioural Neurology, 17, 5–16.PubMedGoogle Scholar
  54. Rowe, W. B., O'Donnell, J. P., Pearson, D., Rose, G. M., Meaney, M. J., & Quirion, R. (2003). Long-term effects of BIBN-99, a selective muscarinic M2 receptor antagonist, on improving spatial memory performance in aged cognitively impaired rats. Behavioural Brain Research, 45, 171–178.CrossRefGoogle Scholar
  55. Rubio, A., Perez, M., & Avila, J. (2006). Acetylcholine receptors and tau phosphorylation. Current Molecular Medicine, 6, 423–428.CrossRefPubMedGoogle Scholar
  56. Sadot, E., Gurwitz, D., Barg, J., Behar, L., Ginzburg, I., & Fisher, A. (1996). Activation of m1-muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. Journal of Neurochemistry, 66, 877–880.PubMedCrossRefGoogle Scholar
  57. Schwarz, R. D., Callahan, M. J., Coughenour, L. L., Dickerson, M. R., Kinsora, J. J., Lipinski, W. J., et al. (1999). Milameline (CI-979/RU35926): A muscarinic receptor agonist with cognition-activating properties: Biochemical and in vivo characterization. The Journal of Pharmacology and Experimental Therapeutics, 291, 812–822.PubMedGoogle Scholar
  58. Spalding, T. A., Trotter, C., Skjaerback, N., Messier, T. L., Currier, E. A., Burstein, E. S., et al. (2002). Discovery of an ectopic activation site on the M(1) muscarinic receptor. Molecular Pharmacology 61, 1297–1302.CrossRefPubMedGoogle Scholar
  59. Sur, C., Mallorga, P. J., Wittmann, M., Jacobson, M. A., Pascarella, D., Williams, J. B., et al. (2003). N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity Proceedings of the National Academy of Sciences of the United States of America, 100, 13674–13679.CrossRefPubMedGoogle Scholar
  60. Svensson, A. L., Alafuzof, I., & Nordberg, A. (1992). Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists. Brain Research, 596, 142–148.CrossRefPubMedGoogle Scholar
  61. Tecle, H., Schwarz, R. D., Barrett, S. D., Callahan, M. J., Caprathe, B. W., Davis, R. E., et al. (2000). CI-1017, a functionally M1-selective muscarinic agonist: Design, synthesis, and preclinical pharmacology. Pharmceutica Acta Helvetiae, 74, 141–148.CrossRefGoogle Scholar
  62. Terry, A. V. Jr., Buccafusco, J. J., Borsini, F., & Leusch, A. (2002). Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist, talsaclidine. Psychopharmacology (Berlin), 162, 292–300.CrossRefGoogle Scholar
  63. Tyler, S. J., Dawbarn, D., Wilcock, G. K., & Allen, S. J. (2002). alpha- and beta-Secretase: Profound changes in Alzheimer's disease. Biochemical and Biophysical Research Communications, 299, 373–376.CrossRefPubMedGoogle Scholar
  64. Van Dam, D., Abramowski, D., Staufenbiel, M., & De Deyn, P. P. (2005). Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model. Psychopharmacology (Berlin), 180, 177–190.CrossRefGoogle Scholar
  65. Vincent, G. P., & Sepinwall, J. (1992). AF102B, a novel M1 agonist, enhanced spatial learning in C57BL/10 mice with a long duration of action. Brain Research, 597, 264–268.CrossRefPubMedGoogle Scholar
  66. Volpicelli, L. A., & Levey, A. I. (2004). Muscarinic acetylcholine receptor subtypes in cerebral cortex and hippocampus. Progress in Brain Research, 145, 59–66.CrossRefPubMedGoogle Scholar
  67. Wanibuchi, F., Konishi, T., Harada, M., Terai, M., Hidaka, K., Tamura, T. et al. (1990). Pharmacological studies on novel muscarinic agonists, 1-oxa-8-azaspiro[4.5]decane derivatives YM796 and YM954. European Journal of Pharmacology, 187, 479–486.CrossRefPubMedGoogle Scholar
  68. Wolf, B. A., Wertkin, A. M., Jolly, Y. C., Yasuda, R. P., Wolfe, B. B., Konrad, R. J., et al. (1995).Muscarinic regulation of Alzheimer's disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. The Journal of Biological Chemistry, 270, 4916–4922.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Abraham Fisher
    • 1
  1. 1.Israel Institute for Biological ResearchIsrael

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