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An Excitotoxic Model of Alzheimer’s Disease: NMDA Lesions and Initial Neural Grafting Results

  • Dennis A. Turner
  • W. Q. Dong
Part of the Advances in Behavioral Biology book series (ABBI, volume 36)

Summary

We have developed an animal model of Alzheimer’s disease, based on a critical loss of neurons which are sensitive to the excitotoxic effects of NMDA glutamate agonists. This model follows an alternative hypothesis for the etiology of the disease, in assuming a global involvement of cortical (and subcortical) neurons with NMDA glutamate receptors, as opposed to a primary subcortical lesion. The initial evaluation of the animal model has included histological assessment and behavioral testing for cortical memory function. Treatment with neural grafting has also been performed, to replace damaged cortical circuitry. The development of animal models of Alzheimer’s disease apart from those with primary cholinergic dysfunction may be helpful for future understanding of the disease manifestations and treatment paradigms.

Keywords

NMDA Receptor Hippocampal Formation Kainic Acid Hippocampal Damage NMDA Glutamate Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Bartus, R. T., Dean, R. L., Beer, B. and Lippa, A. S. (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417.CrossRefGoogle Scholar
  2. 2.
    Hyman, B. T., Van Hoesen, G. W., Damasio, A. R. and Barnes, C. L. (1984) Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science 225: 1168–1170.CrossRefGoogle Scholar
  3. 3.
    Maragos, W. F., Greenamyre, J. T., Penney, J. B. and Young, A. B. (1987) Glutamate dysfunction in Alzheimer’s disease: An hypothesis. TINS 10: 65–68.Google Scholar
  4. 4.
    Perry, E. (1988) Acetylcholine and Alzheimer’s disease. British J. Psychiatry 152: 737–740.CrossRefGoogle Scholar
  5. 5.
    Smith, G. (1988) Animal models of Alzheimer’s disease: experimental cholinergic denervation. Brain Res. Rev. 13: 103–118.CrossRefGoogle Scholar
  6. 6.
    Wilcock, G. K. (1988) Alzheimer’s disease–current issues. Quarterly J. Med. Series 66, No. 250, pp 117–124.Google Scholar
  7. 7.
    Gage, F. H. and Bjorklund, A. (1986) Cholinergic septal grafts into the hippocampal formation improve spatial learning and memory in aged rats by an atropine-sensitive mechanism. J. Neuroscience 6: 2837–2847.Google Scholar
  8. 8.
    Gage, F. H. and Bjorklund, A. (1986) Neural grafting in the aged rat brain. Annual Review of Physiology 48: 447–459.CrossRefGoogle Scholar
  9. 9.
    Gage, F. H., Bjorklund, A., Stenevi, U., Dunnett, S. B. and Kelly, P. A. T. (1984) Intrahippocampal septal grafts ameliorate learning impairments in aged rats. Science 225: 533–536.CrossRefGoogle Scholar
  10. 10.
    Mudrick, L. A., Baimbridge, K. G. and Miller, J. J. (1987) Fetal hippocampal cells transplanted into the ischemically damaged CAl region demonstrate normal characteristics of adult CA1 cells. Neuroscience Abstracts 13: 514.Google Scholar
  11. 11.
    Woodruff, M. L., Baisden, R. H., Whittington, D. L., Shelton, N. L. and Wray, S. (1988) Grafts containing fetal hippocampal tissue reduce activity and improve passive avoidance in hippocampectomized or trimethyltin-exposed rats. Exp. Neurol. 102: 130–143.CrossRefGoogle Scholar
  12. 12.
    Arendash, G. W., Millard, W. J., Dunn, A. J. and Meyer, E. M. (1987) Long-term neuropathological and neurochemical effects of nucleus basalis lesions in the rat. Science 238: 952–956.CrossRefGoogle Scholar
  13. 13.
    Beninger, R. J., Jhamandas, K., Boegman, R.J. and El-Defrawy, S. R. (1986) Kynurenic acid-induced protection of neurochemical and behavioral deficits produced by quinolinic acid injections into the nucleus basalis of rats. Neuroscience Letters, 68: 317–321.CrossRefGoogle Scholar
  14. 14.
    Flicker, C., Dean, R. L., Watkins, D. L., Fisher, S. K. and Bartus, R. T. (1983) Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the cerebral cortex in the rat. Pharmcol. Biochem. Behay. 18: 973–981.CrossRefGoogle Scholar
  15. 15.
    Segal, M. and Milgram, N. W. (1985) Can septal grafting facilitate recovery from physiological and behavioral deficits produced by fornix transections? In: Neural Grafting (ed: Bjorklund, A. ), Elsevier, Amsterdam, pp. 627–637.Google Scholar
  16. 16.
    Tilson, H. A., McLamb, R. L., Shaw, S., Rogers, B.C. Pediaditakis, P. and Cook, L. (1988) Radial-arm maze deficits produced by colchicine administered into the area of the nucleus basalis are ameliorated by cholinergic agents. Brain Res. 438: 83–94.CrossRefGoogle Scholar
  17. 17.
    Wenk, G. L. and Olton, D. S. (1984) Recovery of neocortical choline acetyltransferase activity following ibotenic acid injection into the nucleus basalis Meynert in rats. Brain Res. 293: 184–186.CrossRefGoogle Scholar
  18. 18.
    Cotman, C. W. and Anderson, K. J. (1988) Synaptic plasticity and functional stabilization in the hippocampal formation: possible role in Alzheimer’s disease. In: Advances in Neurology, Vol. 47, Functional Recovery in Neurological Disease (ed: Waxman, S.G. ), Raven, New York, pp. 313–335.Google Scholar
  19. 19.
    Perry, E. K. and Perry, R. H. (1985) New insights into the nature of senile ( Alzheimer-type) plaques. TINS 8: 301–303.Google Scholar
  20. 20.
    Summers, W. K., Majovski, L. V., Marsh, G. M., Tachiki, K. and Kling, A. (1986) Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. NEJM 315: 1241–1245.Google Scholar
  21. 21.
    Wilcock, G. K. and Esiri, M. M. (1982) Plaques, tangles and dementia: A quantitative study. J. Neurol. Sciences 56: 343–356.CrossRefGoogle Scholar
  22. 22.
    Bridges, R. J., Geddes, J. W., Monaghan, D. T. and Cotman, C. W. (1988) Excitatory amino acid receptors in Alzheimer’s disease. In: Excitatory Amino Acids in Health and Disease (ed: Lodge, D. ), John Wiley and Sons, New York, pp. 321–335.Google Scholar
  23. 23.
    Deutsch, S. I. and Morihisa, J. M. (1988) Glutamatergic abnormalities in Alzheimer’s disease and a rationale for clinical trials with L-glutamate. Clinical Neuropharmacology 11: 18–35.CrossRefGoogle Scholar
  24. 24.
    Fagg, G. E., Foster, A. C. and Ganong, A. H. (1986) Excitatory amino acid synaptic mechanisms and neurological function. TIPS 7: 357–363.Google Scholar
  25. 25.
    Greenamyre, J. T., Maragos, W. F., Albin, R. L., Penney, J. B. and Young, A. B. (1988) Glutamate transmission and toxicity in Alzheimer’s disease. Prog. Neuro-Psychopharmacol. and Biol. Psychiat. 12: 421–430.CrossRefGoogle Scholar
  26. 26.
    Greenamyre, J. T., Penney, J. B., D’Amato, C. J. and Young, A. B. (1987) Dementia of the Alzheimer’s type: changes in hippocampal L-[3H] glutamate binding. J. Neurochem. 48: 543–551.CrossRefGoogle Scholar
  27. 27.
    Lester, R. A. J., Herron, C. E., Coan, E. J. and Collingridge, G. L. (1988) The role of NMDA receptors in synaptic plasticity and transmission in the hippocampus. In: Excitatory Amino Acids in Health and Disease (ed: Lodge, D. ), John Wiley and Sons, New York, pp. 275–295.Google Scholar
  28. 28.
    Rothman, S. M. and Olney, J. W. (1987) Excitotoxicity and the NMDA receptor. TINS 10: 299–302.Google Scholar
  29. 29.
    Simpson, M. D. C., Royston, M. C., Deakin, J. F. W., Cross, A. J., Mann, D. M. A. and Slater, P. (1988) Regional Changes in [3H] D-aspartate and [3H] TCP binding sites in Alzheimer’s disease brains. Brain Res. 462: 76–82.CrossRefGoogle Scholar
  30. 30.
    Spencer, P. S., Nunn, P. B., Hugon, J., Ludolph, A. C., Ross, S. M., Roy, D. N. and Robertson, R. C. (1987) Guam amyotrophic lateral sclerosis-Parkinsonism-dementia linked to a plant excitant neurotoxin. Science 237: 517–522.CrossRefGoogle Scholar
  31. 31.
    Squire, L. R. (1986) Mechanisms of memory. Science 232: 1612–1619.CrossRefGoogle Scholar
  32. 32.
    Spencer P. S. (1987) Guam ALS/Parkinsonism-Dementia: A long-latency neurotoxic disorder caused by “slow toxin(s)” in food? Can. J. Neurol. Sci. 14: 347–357.Google Scholar
  33. 33.
    Morris, R. G. M., Garrud, P., Rawlins, J. N. P. and O’Keefe, J. (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297: 681–683.CrossRefGoogle Scholar
  34. 34.
    Morris, R. G. M., Anderson, E., Lynch, G. S. and Baudry, M. (1986) Selective impairment of learning and blockade of long term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319: 774–776.CrossRefGoogle Scholar
  35. 35.
    Morris, R. G. M. (1988) Elements of a hypothesis concerning the participation of hippocampal NMDA receptors in learning. In: Excitatory Amino Acids in Health and Disease (ed: Lodge, D. ), John Wiley and Sons, New York, pp. 297–320.Google Scholar
  36. 36.
    Nadler, J. V., Evenson, D. A. and Cuthbertson, G. J. (1981) Comparative toxicity of kainic acid and other acidic amino acids towards rat hippocampal neurons. Neuroscience 6: 2505–2517.CrossRefGoogle Scholar
  37. 37.
    Morris, R. G. M. (1984) Development of a water-maze procedure for studying spatial learning in the rat. J. Neuroscience Methods 11: 47–60.CrossRefGoogle Scholar
  38. 38.
    Bjorklund, A., Steneví, U., Schmidt, R. H., Dunnett, S. B. and Gage, F. H. (1983) Intracerebral grafting of neuronal cell suspensions 1. Introduction and general methods of preparation. Acta. Physiol. Scand. 522: 1–7.Google Scholar
  39. 39.
    Buzsaki, G., Czopf, J., Kondakor, I., Bjorklund, A. and Gage, F. H. (1987) Cellular activity of intracerebrally transplanted fetal hippocampus during behavior. Neuroscience 22: 871–883.CrossRefGoogle Scholar
  40. 40.
    Gash, D. M. (1987) Neural transplantation: potential therapy for Alzheimer’s disease. J. Neural Transm.(suppl) 24: 301–308.Google Scholar
  41. 41.
    Hounsgaard, J. and Yarom, Y. (1985) Intrinsic control of electroresponsive properties of transplanted mammalian brain neurons. Brain Res. 335: 372–376.CrossRefGoogle Scholar
  42. 42.
    Kimble, D. P., Bremiller, R. and Stickrod, G. (1986) Fetal brain implants improve maze performance in hippocampal-lesioned rats. Brain Res. 363: 358–363.CrossRefGoogle Scholar
  43. 43.
    Raisman, G. and Ebner, F. F. (1983) Mossy fibre projections into and out of hippocampal transplants. Neuroscience 9: 783–801.CrossRefGoogle Scholar
  44. 44.
    Súnde, N. A. and Zimmer, J. (1983) Cellular, histochemical and connective organization of the hippocampus and fascia dentata transplanted to different regions of immature and adult rat brains. Develop. Brain Res. 8: 165–191.CrossRefGoogle Scholar
  45. 45.
    Tonder, N., Sorensen, J. C., Bakkum, E., Danielsen, E. and Zimmer, J. (1988) Hippocampal neurons grafted to newborn rats establish efferent commissural connections. Exp. Brain Res. 72: 577–583.CrossRefGoogle Scholar
  46. 46.
    Lancaster, B. and Wheal, H. V. (1982) A comparative histological and electrophysiological study of some neurotoxins in the rat hippocampus. J. Comp. Neurol. 211: 105–114.CrossRefGoogle Scholar
  47. 47.
    Ransom, B. R., Neale, E., Henkart, M., Bullock, P. N. and Nelson, P. G. (1977) Mouse spinal cord in cell culture. I. Morphology and intrinsic neuronal electrophysiologic properties. J. Neurophysiol. 40: 1132–1150.Google Scholar
  48. 48.
    Reece, L. J. and Schwartzkroin, P. A. (1987) Electrophysiology of morphologically identified septal neurons grafted into rat hippocampus. Neuroscience Abstracts 13: 160.Google Scholar
  49. 49.
    Turner, D. A. (1988) Waveform and amplitude characteristics of evoked responses to dendritic stimulation in CA1 guinea-pig pyramidal cells. J. Physiology (London) 395: 419–439.Google Scholar
  50. 50.
    Cotman, C. W., Monaghan, D. T., Ottersen, O. P. and Storm-Mathisen, J. (1987) Anatomical organization of excitatory amino acid receptors and their pathways. TINS 10: 273–280.Google Scholar
  51. 51.
    Greenamyre, J. T., Young, A. B. and Penney, J. B. (1984) Quantitative autoradiographic distribution of L-[3H]-glutamate-binding sites in rat central nervous system. J. Neurosci. 4: 2133–2144.Google Scholar
  52. 52.
    Davies, P. (1988) Neurochemical studies: An update on Alzheimer’s disease. J. Clin. Psychiatry 49: 23–28.Google Scholar
  53. 53.
    Cowburn, R., Hardy, J., Roberts, P. and Briggs, R. (1988) Regional distribution of pre-and postsynaptic glutaminergic function in Alzheimer’s disease. Brain Res. 452: 403–407.CrossRefGoogle Scholar
  54. 54.
    Danysz, W., Wroblewski, J. T. and Costa, E. (1988) Learning impairment in rats by N-Methyl-D-Aspartate Receptor Antagonists. Neuropharmacology 27: 653–656.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Dennis A. Turner
    • 1
  • W. Q. Dong
    • 1
  1. 1.Department of NeurosurgeryUniversity of Minnesota and Veterans Affairs Medical CenterMinneapolisUSA

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