Skip to main content
Log in

Alzheimer's disease: fundamental and therapeutic aspects

  • Reviews
  • Published:
Experientia Aims and scope Submit manuscript

Abstract

Alzheimer's disease is the most common type of progressive and debilitating dementia affecting aged people. In some early — as well as late-onset familial cases, a genetic linkage with chromosomes 14, 21 (early-onset) or 19 (late-onset) has been indicated. Furthermore, a direct or indirect role has been attributed to normal or structurally altered amyloid β-protein (concentrated in senile plaques) and/or excessively phosphorylated tau protein (located in neurofibrillary tangles). Degeneration of cholinergic neurons and concomitant impairment of cortical and hippocampal neurotransmission lead to cognitive and memory deficits. Several compounds are being tested in attempts to prevent and/or cure Alzheimer's disease, including tacrine, which has very modest efficacy in a sub-group of patients, and new acetylcholinesterase inhibitors. Pilot experiments have also been launched using nerve growth factor (NGF) to prevent or stabilize the processes of cholinergic pathway degeneration. Alternatively, antioxidants, free radical scavengers and/or non steroidal anti-inflammatory agents may be screened as potential therapies for neurodegenerative diseases induced by multiple endogenous and/or exogenous factors. The recent use of transgenic mice, in parallel with other genetic, biochemical and neurobiological systems, in vivo and/or in vitro (cell cultures), should accelerate the discovery and development of specific drugs for the treatment of Alzheimer's disease.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

ReferencesReferences

  1. Ashall, F., and Goate, A.M., Role of the β-amyloid precursor protein in Alzheimer's disease. Trends biochem. Sci.19 (1994) 42–46.

    Article  CAS  PubMed  Google Scholar 

  2. Barinaga, M., Neurotrophic factors enter the clinic. Science264 (1994) 772–774.

    Article  CAS  PubMed  Google Scholar 

  3. Boddeke, E., Hugtenburg, J., Jap, W., Heynis, J., and Van Zwieten, P., New anti-ischaemic drugs: cytoprotective action with no primary haemodynamic effects. Trends pharmac. Sci.10 (1989) 397–400.

    Article  CAS  Google Scholar 

  4. Borroni, E., Damsma, G., Giovacchini, C. Mutel, V., Jakob-Rötne, R., and Da Prada, M., A novel acetylcholinesterase inhibitor, Ro 46-5934, which interacts with muscarinic M2 receptors. Biochem. Soc. Trans.22 (1994) 755–758.

    Article  CAS  PubMed  Google Scholar 

  5. Buttke, T.M., and Sandstrom, P.A., Oxidative stress as a mediator of apoptosis. Immunol. Today15 (1994) 7–10.

    Article  CAS  PubMed  Google Scholar 

  6. Chatellier, G., and Lacomblez, L., Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. Br. med. J.300 (1990) 495–499.

    Article  CAS  Google Scholar 

  7. Choi, D.W., Foe or friend to the injured brain? Proc. natl Acad. Sci. USA90 (1993) 9741–9743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chun, M.R., and Mayeux, R., Alzheimer's disease. Curr Opin. Neurol.7 (1994) 299–304.

    Article  CAS  PubMed  Google Scholar 

  9. Collerton, D., Cholinergic function and intellectual decline in Alzheimer disease. Neurosci.19 (1986) 1–28.

    Article  CAS  Google Scholar 

  10. Cook, P., and James, I., Cerebral vasodilators. New Engl. J. Med.305 (1981) 1508–1513; 1560–1564.

    Article  CAS  PubMed  Google Scholar 

  11. Coyle, J.T., and Puttfarcken, P., Oxidative stress, glutamate, and neurodegenerative disorders. Science262 (1993) 689–695.

    Article  CAS  PubMed  Google Scholar 

  12. Cummings, J.L., Clinical features and treatment of Alzheimer's disease. Curr. Opin. Neurol. Neurosurg.3 (1990) 90–97.

    Google Scholar 

  13. Davis, K.L., Thal, L.J., Gamzu, E.R., Davis, C.S., Woolson, R.F., Gracon, S.I., et al., A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer's disase. New Engl. J. Med.327 (1992) 1253–1259.

    Article  CAS  PubMed  Google Scholar 

  14. Eagger, S.A., Levy, R., and Sahakian, B.J., Tacrine in Alzheimer's disease. Lancet337 (1991) 989–992.

    Article  CAS  PubMed  Google Scholar 

  15. Faden, A.I., and Salzman, S., Pharmacological strategies in CNS trauma. Trends pharmac. Sci.13 (1992) 29–35.

    Article  CAS  Google Scholar 

  16. Farlow, M., Gracon, S.I., Hershey, L.A., Lewis, K.W., Sadowsky, C.H., and Dolan-Ureno, J., A controlled trial of tacrine in Alzheimer's disease. J. Am. med. Ass.268 (1992) 2523–2529.

    Article  CAS  Google Scholar 

  17. Franssen, E.H., Kluger, A., Torossian, C.L., and Reisberg, B., The neurologic syndrome of severe Alzheimer's disease Relationship to functional decline. Archs Neurol.50 (1993) 1029–1039.

    Article  CAS  Google Scholar 

  18. Gandy, S., and Greengard, P., Amyloidogenesis in Alzheimer's disease: some possible therapeutic opportunities. Trends pharmac. Sci.13 (1992) 108–113.

    Article  CAS  Google Scholar 

  19. Garcia, I., Martinou, I., Tsujimoto, Y., and Martinou, J.C., Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science258 (1992) 302–304.

    Article  CAS  PubMed  Google Scholar 

  20. Garthwaite, J., Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci.14 (1991) 60–67.

    Article  CAS  PubMed  Google Scholar 

  21. Gauthier, S., Bouchard, R., Lamontagne, A., Bailey, P., Bergman, H., et al., Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease. New Engl. J. Med.322 (1990) 1272–1276.

    Article  CAS  PubMed  Google Scholar 

  22. Gentleman, S.M., Graham, D.I., and Roberts, G.W., Molecular pathology of head trauma: altered βAPP metabolism and the aetiology of Alzheimer's disease. Prog. Brain Res.96 (1993) 237–246.

    Article  CAS  PubMed  Google Scholar 

  23. Giacobini, E., Pharmacotherapy of Alzheimer's disease: New drugs and novel strategies, in: Alzheimer's Disease: Advances in Clinical and Basic Research, pp. 529–538. Eds B. Corain, K. Iqbal, M. Nicolini, B. Winblad, H. Wisniewski and P. Zatta. John Wiley & Sons Ltd. Chichester-New York-Brisbane-Toronto, Singapore 1993.

    Google Scholar 

  24. Goa, K.L., and Fitton, A., Velnacrine in Alzheimer's disease. CNS Drugs1 (1994) 232–240.

    Article  CAS  PubMed  Google Scholar 

  25. Goate, A., Chartier-Harlin, M.C. Mullan, M., Brown, J., Crawford, F., Fidani, L. et al., Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature349 (1991) 704–706.

    Article  CAS  PubMed  Google Scholar 

  26. Goedert, M., Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci.16 (1993) 460–465.

    Article  CAS  PubMed  Google Scholar 

  27. Haass, C., and Selkoe, D.J., Cellular processing of β-amyloid precursor protein and the genesis of amyloid-β-peptide. Cell75 (1993) 1039–1042.

    Article  CAS  PubMed  Google Scholar 

  28. Hall, E.D., Cerebral ischaemia, free radicals and antioxidant protection. Biochem. Soc. Trans.21 (1993) 334–339.

    Article  CAS  PubMed  Google Scholar 

  29. Hammond, R.R., Gage, F.H., and Terry, R.D., Alzheimer's disease and spirochetes; a questionable relationship. NeuroReport4 (1993) 840.

    Article  CAS  PubMed  Google Scholar 

  30. Haxby, J.V., Grady, C.L., Duara, R., Schlageter, N., Berg, G., and Rapoport, S.I., Neocortical metabolic abnormalities precede nonmemory cognitive defects in early Alzheimer's-type dementia. Archs Neurol.43 (1986) 882–885.

    Article  CAS  Google Scholar 

  31. Heise, G.A., Facilitation of memory and cognition by drugs. Trends pharmac. Sci.8 (1987) 65–68.

    Article  CAS  Google Scholar 

  32. Hirsch, D.B., Steiner, J.P., Dawson, T.M., Mammen, A., Hayek, E., and Snyder, S.H., Neurotransmitter release regulated by nitric oxide in PC-12 cells and brain synaptosomes. Curr. Biol.3 (1993) 749–754.

    Article  CAS  PubMed  Google Scholar 

  33. Hockenbery, D.M. Oltvai, Z.N., Yin, X.-M., Milliman, C.L., and Korsmeyer, S.J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell75 (1993) 241–251.

    Article  CAS  PubMed  Google Scholar 

  34. Hoyer, S., Abnormalities in brain glucose utilization and its impact on cellular and molecular mechanisms in sporadic dementia of Alzheimer type, in: Alzheimers Disease: Amyloid Precursor Proteins, Signal Transduction, and Neuronal Transplantation, Ann. N.Y. Acad. Sci., vol. 695, pp. 77–80. Eds R.M. Nitsch, J.H. Growdon, S. Corkin, and R.J. Wurtman, New York Acad. Sciences, New York 1993.

    Google Scholar 

  35. Hung, A.Y., Haass C., Nitsch, R.M., Qiu, W.Q., Citron, M., Wurtman, R.J., Growdon, J.H., and Selkoe, D.J., Activation of protein kinase C inhibits cellular production of the amyloid β-protein. J. biol. Chem.268 (1993) 22959–22962.

    Article  CAS  PubMed  Google Scholar 

  36. Kane, D.J., Sarafian, T.A., Anton, R., Hahn, H., Gralla, E.B., Valentine, J.S., Örd, T., and Bredesen, D.E., Bcl-2 inhibition of neural death: decreased generation of reative oxygen species. Science262 (1993) 1274–1277.

    Article  CAS  PubMed  Google Scholar 

  37. Katzman, R., and Saitoh, T., Advances in Alzheimer's disease. FASEB. J.5 (1991) 278–286.

    Article  CAS  PubMed  Google Scholar 

  38. Korsmeyer, S.J., Shutter, J.R., Veis, D.J., Merry, D.E., and Oltvai, Z.N., Bcl-2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Sem. in Cancer Biol.4 (1993) 327–332.

    CAS  Google Scholar 

  39. Lamb, B.T., Sidodia, S.S., Lawler, A.M., Slunt, H.H., Kitt, C.A., Kearns, W.G. et al.., Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice. Nat. Genet.5 (1993) 22–30.

    Article  CAS  PubMed  Google Scholar 

  40. Lamy, P.P., The role of cholinesterase inhibitors in Alzheimer's disease. CNS Drugs1 (1994) 146–165.

    Article  Google Scholar 

  41. Lapchak, P.A., Nerve groth factor pharmacology: Application to the treatment of cholinergic neurodegeneration in Alzheimer's disease. Expl. Neurol.124 (1993) 16–20.

    Article  CAS  Google Scholar 

  42. Lee, V.M.-Y., Balin, B.J., Otvos, L. Jr., and Trojanowski, J.Q., A68: a major subunit of paired helical filaments and derivatized forms of normal tau. Science251 (1991) 675–678.

    Article  CAS  PubMed  Google Scholar 

  43. Lemke, M., Frei, B., Ames, B.N., and Faden, A.I., Decreases in tissue levels of ubiquinol-9 and 10, ascorbate and α-tocopherol following spinal cord impact trauma in rats. Neurosci. Lett.108 (1990) 201–206.

    Article  CAS  PubMed  Google Scholar 

  44. Lowe, G.D.O., Drugs in cerebral and peripheral arterial disease. Lancet300 (1990) 524–528.

    CAS  Google Scholar 

  45. Mandelkow, E.-M., and Mandelkow, E., Tau as a marker for Alzheimer's disease. Trends biochem. Sci.18 (1993) 480–483.

    Article  CAS  PubMed  Google Scholar 

  46. Martin, S.J., Green, D.R., and Cotter, T.G., Dicing with death: dissecting the components of the apoptosis machinery. Trends biochem. Sci.19 (1994) 26–30.

    Article  CAS  PubMed  Google Scholar 

  47. Marx, J., Alzheimer's debate boils over. Science257 (1992) 1336–1338.

    Article  CAS  PubMed  Google Scholar 

  48. Mattson, M.P., Cheng, B., and Smith-Swintosky, V.L., Mechanisms of neurotrophic factor protection against calcium-and free radical-mediated excitotoxic injury: implications for treating neurodegenerative disorders. Expl Neurol.124 (1993) 89–95.

    Article  CAS  Google Scholar 

  49. Miklossy, J., Alzheimer's disease — a spirochetosis? NeuroReport4 (1993) 841–848.

    Article  CAS  PubMed  Google Scholar 

  50. Miklossy, J., Kasas, S., Janzer, R.C., Ardizzoni, F., and Van der Loos, H., Further ultrastructural evidence that spirochaetes may play a role in the aetiology of Alzheimer's disease. NeuroReport5 (1994) 1201–1204.

    Article  CAS  PubMed  Google Scholar 

  51. Molloy, D.W., and Cape, R.D.T., Acute effects of oral pyridostigmine on memory and cognitive function in SDAT. Neurobiol. Aging10 (1989) 199–204.

    Article  CAS  PubMed  Google Scholar 

  52. Mullan, M., and Crawford, F., Genetic and molecular advances in Alzheimer's disease. Trends Neurosci.16 (1993) 398–402.

    Article  CAS  PubMed  Google Scholar 

  53. Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., and Ikeda, K., Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res.541 (1991) 163–166.

    Article  CAS  PubMed  Google Scholar 

  54. Nieto, A., Montejo de Garcini, E., Correas, I. and Avila, J., Characterization of tau protein present in microtubules and paired helical filaments of Alzheimer's disease patients's brain. Neuroscience37 (1990) 163–170.

    Article  CAS  PubMed  Google Scholar 

  55. Olanow, C.W., A radical hypothesis for neurodegeneration. Trends Neurosci.16 (1993) 439–444.

    Article  CAS  PubMed  Google Scholar 

  56. Olson, L., NGF and the treatment of Alzheimer's disease. Expl. Neurol.124 (1993) 5–15.

    Article  CAS  Google Scholar 

  57. Palmer, A.M., and DeKosky, S.T., Monoamine neurons in aging and Alzheimer's disease. J. neural Transm.91 (1993) 135–159.

    Article  CAS  Google Scholar 

  58. Pearson, B.E., and Choi, T.K., Expression of the human β-amyloid precursor protein gene from a yeast artificial chromosome in transgenic mice. Proc. natl Acad. Sci. USA90 (1993) 10578–10582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Pollard, H.B., Rojas, E., and Arispe, N., β-Amyloid in Alzheimer's disease. CNS Drugs2 (1994) 1–6.

    Article  Google Scholar 

  60. Raff, M.C., Barres, B.A., Burne, J.F., Coles, H.S., Ishizaki, Y., and Jacobson, M.D., Programmed cell death and the control of cell survival: Lessons from the nervous system. Science262 (1993) 695–700.

    Article  CAS  PubMed  Google Scholar 

  61. Reed, J.C., Bcl-2 and the regulation of programmed cell death. J. Cell Biol.124 (1994) 1–6.

    Article  CAS  PubMed  Google Scholar 

  62. Roberts, F., and Lazareno, S., Cholinergic treatments for Alzheimer's disease. Biochem. Soc. Trans.17 (1989) 76–79.

    Article  CAS  PubMed  Google Scholar 

  63. Rogers, J., Kirby, L.C., Hempelman, S.R., Berry, D.L., McGeer, P.L., Kaszniak, A.W., Zalinski, J., Cofield, M., Mansukhani, L., Willson, P., and Kogan, F., Clinical trial of indomethacin in Alzheimer's disease. Neurology43 (1993) 1609–1611.

    Article  CAS  PubMed  Google Scholar 

  64. Rogers, J., Inflammation and Alzheimer's disease. CNS Drugs1 (1994) 241–244.

    Article  Google Scholar 

  65. Royston, M.C., Rothwell, N.J., and Roberts, G.W., Alzheimer's disease: pathology to potential treatments? Trends pharmac. Sci.13 (1992) 131–133.

    Article  CAS  Google Scholar 

  66. Schmechel, D.E., Saunders, A.M., Strittmatter, W.J., Crain, B.J., Hulette, C.M., Joo, S.H., Pericak-Vance, M.A., Goldgaber, D., and Roses, A.D., Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. natl Acad. Sci. USA90 (1993) 9649–9653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schubert, D., Kimura, H., and Maher, P., Growth factors and vitamin E modify neuronal glutamate toxicity Proc. natl Acad. Sci. USA89 (1992) 8264–8267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Selkoe, D.J., Biochemistry of altered brain proteins in Alzheimer's disease. A. Rev. Neurosci.12 (1989) 463–490.

    Article  CAS  Google Scholar 

  69. Selkoe, D.J., Physiological production of the β-amyloid protein and the mechanism of Alzheimer's disease. Trends Neurosci.16 (1993) 403–409.

    Article  CAS  PubMed  Google Scholar 

  70. Shutske, G.M., Pierrat, F.A., Cornfeldt, M.L., Szewczak, M.R., Huger, F.P., Bores, G.M., Harontanian, V., and Davis, K.L., (±)-9-Amino-1,2,3,4-tetrahydroacridin-1-ol. A potential Alzheimer's disease therapeutic of low toxicity. J. med. Chem.31 (1988) 1278–1279.

    Article  CAS  PubMed  Google Scholar 

  71. Sies, H., Strategies of antioxidant defense. Eur. J. Biochem.215 (1993) 213–219.

    Article  CAS  PubMed  Google Scholar 

  72. Slotkin, T.A., Nemeroff, C.B., Bissette, G., and Seidler, F.J., Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies. J. clin. Invest.94 (1994) 696–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Spagnoli, A., and Tognoni, G., “Cerebroactive” drugs. Clinical pharmacology and therapeutic role in cerebrovascular disorders. Drugs26 (1983) 44–69.

    Article  CAS  PubMed  Google Scholar 

  74. Steiner, B., Mandelkow, E.M., Biernat, J., Gustke, N., Meyer, H.E., Schmidt, B., Mieskes, G., Söling, H.D., Drechsel, D., Kirschner, M.W., Goedert, M., and Mandelkow, E., Phosphorylation of microtubules associated protein tau: identification of the site for Ca+-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J.9 (1990) 3539–3544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Summers, W.K., Majovski, L.V., Marsh, G.M., Tachiki, K., and Kling, A., Oral tetrahydroaminoacridine in long-term treatment of senile dementia. New Engl. J. Med.315 (1986) 1241–1245.

    Article  CAS  PubMed  Google Scholar 

  76. Uterman, G. The apolipoprotein E connection. Curr. Biol.4 (1994) 362–365.

    Article  Google Scholar 

  77. Vincent, I.J., and Davies, P., A protein kinase associated with paired helical filaments in Alzheimer's disease. Proc. natl Acad. Sci USA89 (1992) 2878–2882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Walsh, T.J., Site-specific pharmacology for the treatment of Alzheimer's disease. Expl Neurol.124 (1993) 43–46.

    Article  CAS  Google Scholar 

  79. Watkins, P.B., Zimmerman, H.J., Knapp, M.J., Gracon, S.I., and Lewis, K.W., Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. J. Am. med. Assoc.271 (1994) 992–998.

    Article  CAS  Google Scholar 

  80. Wenk, G.L., Animal models of Alzheimer's disease, in: Animal Models of Neurological Disease, I Neurodegenerative Diseases, vol. 21, pp. 29–63. Eds A.A. Boulton, G.B. Baker, and R.F. Butterworth Neuromethods, Humana Press, Totowa, New Jersey 1992.

    Chapter  Google Scholar 

  81. Wink, D.A., Hanbauer, I., Krishna, M.C., De Graff, W., Gamson, J., and Mitchell, J.B., Nitric oxide protects against cellular damage and cytotoxicity from reactive oxygen species. Proc. natl Acad. Sci. USA90 (1993) 9813–9817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yoshida, S., and Suzuki, N., Antiamnesic and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats. Eur. J. Pharmac.250 (1993) 117–124.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schorderet, M. Alzheimer's disease: fundamental and therapeutic aspects. Experientia 51, 99–105 (1995). https://doi.org/10.1007/BF01929348

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01929348

Key words

Navigation