Alzheimer Disease

From Molecular Biology to Therapy
  • Ezio Giacobini
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 429)


The systematic development of Alzheimer Disease (A.D.) therapy is only ten year old. It was initiated on a large scale following the publication in New England Journal of Medicine of the first successful results obtained with the cholinesterase inhibitor (ChEI) tacrine, (THA, tetrahydroaminoacridine) by Summers et al. (1986). Numerous studies (cf. Becker et al. 1991) had been performed previously, particularly in USA, in small groups of patients, with physostigmine (physo) alone or in combination with lecithine. Physostigmine, like tacrine, showed definite but only shortlasting improvements of cognitive symptoms (attention, concentration, memory) which were accompanied with severe peripheral and central cholinergic side effects. These consisted mainly of gastro-intestinal symptoms and drowsiness but in the case of tacrine also of liver toxicity. Physostigmine and tacrine represent important milestones in AD therapy as they supported in the patient, the pharmacological hypothesis formulated in the experimental animal (Mattio et al. 1986; Giacobini, 1987; Hallak and Giacobini, 1986; Giacobini et al. 1986) that a treatment improving function of the central cholinergic system obtained through an increase of brain ACh would also improve cognition in AD patients. Targeting the cholinergic system for AD therapy does not necessarily limit itself to use a cholinesterase inhibitor (ChEI). Two other classes of cholinergic drugs might represent valid alternatives such as nicotinic and muscarinic agonists alone or in combination with ChEI (Fig 1). A second, non-cholinergic approach, is based on the classic pathological landmarks of the disease aiming to decrease beta-amyloid (beta-A4) deposition and amyloidogenic APP (Amyloid Precursor Protein) release in brain (Fig 1).


Alzheimer Disease Cholinesterase Inhibitor Cholinergic System Nursing Home Placement Central Cholinergic System 
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  1. Allain, H., Maruelle, L., Beneton, C., Rouault,G., and Belliard, S. (1996). Acute episodes of high blood pressure with tacrine. Presse Medicale 25: 30 pp 1388–1389.Google Scholar
  2. Amberla, K., Nordberg, A., Viitanen, M., and Winblad, B. (1993). Long-term treatment with tacrine (THA) in Alzheimer’s disease–evaluation of neuropsychological data. Acta Neurologica Scandinavica Supplement 149 pp 55–57.Google Scholar
  3. Anderson, J.P., Refolo, L.M., Wallace, W., Mehta, P., Krishnamurthi, M., Gotlib, J., Bierer, L., Haroutunian, V, Perl, D. and Robakis, N.K. (1989). Differential brain expression of the Alzheimer’s amyloid precursor protein. EMBO Journal 8: pp 3627–3632.PubMedGoogle Scholar
  4. Becker, R., Moriearty, P., and Unni, L. (1991). The second generation of cholinesterase inhibitors: Clinical and pharmacological effects In Cholinergie basis for Alzheimer Therapy pp 263–296. Edited by Becker, R. and Giacobini, E., Boston: Birkhäuser.Google Scholar
  5. Beeson, J.G., Shelton, E.R., Chan, H.W. and Gage, F.H. (1994). Differential distribution of amyloid protein precursor immunoreactivity in the rat brain studied by using five different antibodies. Journal of Comparative Neurology 342: pp 78–96.PubMedCrossRefGoogle Scholar
  6. Biyah, K., Molimard, M, Naline, E., Bazelly. B., and Advenier, C. (1996). Indirect muscarinic receptor activation by pentamidine on airway smooth muscle British Journal of Pharmacology 119:6 pp 1 131-I 136.Google Scholar
  7. Buxbaum, J.D., Oishi, M., Chen, H.I., Pinkas-Kramarski, R., Jaffe, E.A., Gandy, S.E. and Greengard. P. (1992). Cholinergie agonists and interleukin l regulate processing and secretion of the Alzheimer 13A4 amyloid protein precursor. Proceedings of National Academy of Science, USA 89: pp 10075–10078.CrossRefGoogle Scholar
  8. Buxbaum, J.D. (1995). Post-translational control of the amyloid b-protein precursor processing. In Pathobiology of Alzheimer’s Disease, Academic Press Limited, pp 98–114.Google Scholar
  9. Checler, F. (1995). Processing of the b-amyloid precursor protein and its regulation in Alzheimer’s disease. Journal of Neurochemistry 65: 4 pp 1431–1444.PubMedCrossRefGoogle Scholar
  10. Chong, Y.H. and Suh, Y.H. (1996). Amyloidogenic processing of Alzheimer’s amyloid precursor protein in vitro and its modulation by metal ions and tacrine. Life Science 59 /7 pp 545–557.CrossRefGoogle Scholar
  11. Eagger, S., Richards, M., and Levy, R. (1994). Long-term effects of tacrine in Alzheimer’s disease: an open study. International Journal of Geriatric Psychiatry 9 pp 643–647.CrossRefGoogle Scholar
  12. Feldman, S., and Karalliedde, L. (1996). Drug interactions with neuromuscular blockers. Drug-Safety 15: 4 pp 261–273.PubMedCrossRefGoogle Scholar
  13. Giacobini, E. (1987). Models and strategies of cholinomimetic therapy of Alzheimer disease. In Cellular and molecular basis of cholinergic function, pp 882–901. Edited by Dowdall, M.J. and Hawthorne, J.N. England: Ellis Horwood.Google Scholar
  14. Giacobini, E. (1996a). Closer to the truth about ApoE-4. Alzheimer Insights 2 /2 pp 1–4.Google Scholar
  15. Giacobini, E. (1996b). Cholinesterase inhibitors do more than inhibit cholinesterase. In Alzheimer Disease: From Molecular Biology to Therapy (pp 187–204 ). Edited by Becker, R. and Giacobini, E., Boston: Birkhäuser.Google Scholar
  16. Giacobini, E., Becker, R., Elble, T., Mattio, M., Mcllhany, M. and Scarsella, G. (1987). Brain acetylcholine — A view from the cerebrospinal fluid. In Neurobiology of Acetylcholine (pp 85–101). Edited by Dun, N., New York: Plenum Press.Google Scholar
  17. Giacobini, E. and Cuadra, G. (1994). Second and third generation cholinesterase inhibitors: From preclinical studies to clinical efficacy. In: Alzheimer Disease: Therapeutic Strategies (pp. 155–171 ). Edited by Giacobini. E. and Becker, R., Boston: Birkhäuser.CrossRefGoogle Scholar
  18. Giacobini, E., Mori, F., Buznikov, A. and Becker, R. (1995). Cholinesterase inhibitors alter APP secretion and APP mRNA in rat cerebral cortex. Society of Neuroscience Abstracts 21 pp 988.Google Scholar
  19. Giacobini, E., Zhu, X.D., Williams, E., and Sherman, K.A. (1996). The effect of the selective reversible acethylcholinesterase inhibitor E2020 on extracellular acetylcholine and biogenic amines levels in rat cortex. Neuropharmacology 35 (2) pp 205–211.PubMedCrossRefGoogle Scholar
  20. Gracon, S., Smith, F. and Hoover, T. (1996). Long-term tacrine treatment: Effect on nursing home placement and mortality. In Alzheimer Disease: From Molecular Biology to Therapy (pp 205–209 ). Edited by Becker, R. and Giacobini, E. Boston: Birkhäuser.Google Scholar
  21. Hallak, M. and Giacobini, E. (1986). Relation of brain regional physostigmine concentrations to cholinesterase activity, and acetylcholine and choline levels in rat. Neurochemistry Research 11 pp 1037–1048.CrossRefGoogle Scholar
  22. Haroutunian, V., Greig, N., Pei, X.F., Utsuki, L., Acevedo, L.D., Gluck, R., Davis, K.L. and Wallace, D. (1996). Pharmacological modulation of Alzheimer’s b-amyloid precursor protein levels in the CSF of rats with forebrain cholinergic system lesions. Society for Neuroscience 22 461.7 pp 1169.Google Scholar
  23. Haroutunian, V., Greig, N.H., Gluck, R., Fiber, E., Davis, K.L. and Wallace, W.C. (1995). Selective attenuation of lesion-induced increases in secreted b-APP by acetylcholinesterase inhibitors. Society for Neuroscience 21 208.1 pp 5.Google Scholar
  24. Hoshi, M, Takashima, A., Murayama, M., Yasutake, K., Yoshida, N., Ishiguro, K., Hoshino, T. and Imahori K. (1997). Nontoxic amyloid beta peptide (1–42) suppresses acetylcholine synthesis. Possible role in cholinergic dysfunction in Alzheimer’s disease. Journal of Biological Chemistry 272 /4 pp 2038–2041.PubMedCrossRefGoogle Scholar
  25. Imbimbo, B.P., Perini, M., Verdelli, G., and Troetel, W.M. (1997). Two year treatment of Alzheimers’s disease with eptastigmine. International Congress of Neurology (Buenos Aires)Abstracts.Google Scholar
  26. Kang, J., Lemaire, H.G., Unterbeck, A., Salbaum, J.M., Master, C.L., Grzeschil, K.H., Multaup, G., Beyreuther, K. and Muller-Hill, B. (1987). The precursor of Alzheimer disease amyloid A4 protein resembles a cell-surface receptor. Nature 325 pp 733–736.PubMedCrossRefGoogle Scholar
  27. Knopman, D., Schneider, L., Davis, K., Talwalker, S., Smith, F., Hoover, T. and Gracon, S. (1996). Long-term tacrine treatment. Neurology 47 pp 166–177.PubMedCrossRefGoogle Scholar
  28. Lahiri, D.K., Lewis, S. and Farlow, M.R. (1994). Tacrine alters the secretion of the beta-amyloid precursor protein in cell lines. Journal of Neuroscience Research 37 pp 777–787.PubMedCrossRefGoogle Scholar
  29. Lebert, F., Hasenbroekx, C., Pasquier, F., and Petit, H. (1996). Convulsive effects of tacrine. Lancet 347 pp 1339–1340.PubMedCrossRefGoogle Scholar
  30. Maany, I. (1996). Adverse interaction of tacrine and haloperidol. Americann Journal of Psychiatry 153: 11 pp 1504.Google Scholar
  31. Mattio, T., Mcllhany, M., Giacobini, E. and Hallak, M. (1986). The effects of Physostigmine on acetylcholinesterase activity of CSF, plasma and brain. A comparison of intravenous and intraventricular administration in beagle dogs. Neuropharmacology 25 pp 1167–1177.PubMedCrossRefGoogle Scholar
  32. McSwain, ML., and Forman LM. (1995). Severe parkinsonian symptom development on combination treatment with tacrine and haloperidol (letter). Journal of Clinical Psychopharmacology 15 pp: 284.Google Scholar
  33. Minthon, L, Nilsson, K., Edvinsson, L., Wendt, P.E. and Gustafson, L. (1995). Long-term effects of tacrine on regional cerebral blood flow changes in Alzheimer’s Disease. Dementia 6 pp 245–251.PubMedGoogle Scholar
  34. Mori, F., Cuadra, G. and Giacobini, E. (1995b). Metrifonate effects on acetylcholine and biogenic amines in rat cortex. Neurochemistry Research 20 (9) pp 1081–1088.CrossRefGoogle Scholar
  35. Mori, F., Lai, C.C., Fusi, F. and Giacobini, E. (1995a). Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neuro Report 6 (4) pp 633–636.CrossRefGoogle Scholar
  36. Nitsch, R.M., Farber, S.A., Growdon, J.H. and Wurtman, R.J. (1993). Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices. Proceeding of National Academy of Science, USA, 90 pp 191–193.Google Scholar
  37. Nitsch, R.M. and Growdon, J.H. (1994). Role of neurotransmission in the regulation of amyloid beta-protein precursor processing. Biochemical Pharmacology 47 (8): 1275.PubMedCrossRefGoogle Scholar
  38. Nordberg, A. (1993). Clinical studies in Alzheimer patients with positron emission tomography. Elsevier Science Publishers, Behavioural Brain Research 57 pp 215–224.PubMedCrossRefGoogle Scholar
  39. Nordberg, A. (1995). Long term treatment effects on progression of Alzheimer’s disease as determined by functional brain studies. In Research Advances in Alzheimer’s disease and Related Disorders (pp 293–298). Edited by Ikbal, K., Mortimer, J.A., Winblad, B., Wiesniewski, H.M. Chichester: John & Sons.Google Scholar
  40. Poirier, J., Delisle, M.C., Quirion, R., Aubert, I., Farlow, M., Lahiri, D., Hui, S., Bertrand, P., Nalbantoglu, J., Gil-fix, B.M. and Gauthier, S. (1995). Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. Proceeding of National Academy of Science 92 pp 12260–1226.CrossRefGoogle Scholar
  41. Paddle, B. and Dowling, M. (1996). Blockade of nicotinic responses by anticholinesterases. General Pharmacology 27: 5 pp 861–872.PubMedCrossRefGoogle Scholar
  42. Roses, A. (1995). Perspective on the metabolism of apolipoprotein E and the Alzheimer disease. Experimental Neurology 132 pp 149–156.CrossRefGoogle Scholar
  43. Sandbrink, R., Hartmann, T., Masters, C.L. and Beyreuther, K. (1996). Genes contribution to Alzheimer’s disease. Molecular Psychiatry 1 pp 27–40.PubMedGoogle Scholar
  44. Soininen, H., Kosunen, O., Helisalmi, S., Mannermaa, A., Paljärvi, L., Talasniemi, S., Ryynänen, M. and Riekkinen, P., Sr. (1995). A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein e4 allele. Neuroscience Letters 187 pp 79–82.PubMedCrossRefGoogle Scholar
  45. Soininen, H., and Riekkinen, J. Sr (1996). Apolipoprotein E, memory and Alzheimer’s disease. Trends in Neursoscience 19 pp 224–228.CrossRefGoogle Scholar
  46. Solomon, P., Knapp, M., Gracon, S., Groccia, M. and Pendlebury, W. (1996). Long-term tacrine treatment in patients with Alzheimer’s disease. Lancet 348 pp 275–276.PubMedCrossRefGoogle Scholar
  47. Van Broeckhoven, C. (1995). Presenilins and Alzheimer disease. Nature Genetics 11 pp 230–232.PubMedCrossRefGoogle Scholar
  48. Vito, P., Lacanâ, E. and D’Adamio, L. (1996). Interfering with apoptosis: Ca2+ -binding protein ALG-2 and Alzheimer’s disease gene ALG-3. Science 271 pp 521–525.PubMedCrossRefGoogle Scholar
  49. Wilcock, G., Scott, M. and Pearsall, T. (1994). Long-term use of tacrine. Lancet 343 pp 294.PubMedCrossRefGoogle Scholar
  50. Yankner, B (1996). New clues to Alzheimer’s disease: Unraveling the roles of amyloid and tau. Nature Medicine 2. 8 pp 850–852.PubMedCrossRefGoogle Scholar
  51. Zaborsky, L. and W.E. Cullinan, (1996). Direct cathecholaminergic-cholinergic interactions in the basal forebram.l. Dopamine-beta-hydroxylase input to cholinergic neurons. Journal of Comparative Neurology 374 pp 5345–554.Google Scholar
  52. Zhu, X.D., Giacobini, E. and Hornsperger, J.M. (1995). Effect of MDL 73,745 on acetylcholine and biogenic amine levels in rat cortex. European Journal of Pharmacology 276 pp 93–99.PubMedCrossRefGoogle Scholar
  53. Zhu, X.D., Cuadra, G., Brufani, M., Maggi, T., Pagella, P.G., Williams, E. and Giacobini, E. (1996). Effects of MF268, a new cholinesterase inhibitor, on acetylcholine and biogenic amines in rat cortex. Journal of Neuroscience Research 43 pp 120–126.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Ezio Giacobini
    • 1
  1. 1.HUG, Belle-Idée, Department of GeriatricsUniversity Hospitals of GenevaThonex, GenevaSwitzerland

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