Transneuronal Neurochemical and Neuropathological Changes Induced by Nucleus Basalis Lesions: A Possible Degenerative Mechanism in Alzheimer’s Disease

  • Gary W. Arendash
  • Gregory J. Sengstock
  • Gerry Shaw
  • William J. Millard
Part of the Advances in Behavioral Biology book series (ABBI, volume 36)


A considerable body of evidence indicates that neurons within a number of CNS systems may atrophy or degenerate following a loss of their afferents (1). This transneuronal atrophy or degeneration secondary to deafferentation is commonly referred to as “anterograde transneuronal degeneration.” Perhaps the best example of this phenomenon is the atrophy/degeneration of neurons within the lateral geniculate nucleus following interruption of their afferent input from the optic nerve (2). Such transneuronal changes may occur very slowly, often taking months or years to manifest themselves. Although the mechanism(s) responsible for atrophy or degeneration of neurons which have suffered no direct injury are basically unknown, a likely mechanism involves loss of a neurotransmitter and/or neurotrophic factor(s) formerly released onto these neurons by eliminated afferent nerve terminals.


Entorhinal Cortex Cholinergic Neuron Vasoactive Intestinal Polypeptide Nucleus Basalis Bilateral Lesion 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cowan, W.M. (1970) Anterograde and retrograde transneuronal degeneration in the central and peripheral nervous system. In: Contemporary Research Methods in Neuroanatomy (eds: Nauta, W. and Ebbesson, S.) Springer-Verlag, New York, pp. 217–236.CrossRefGoogle Scholar
  2. 2.
    Kupfer, C. (1965) The distribution of cell size in the lateral geniculate nucleus of man following transneuronal cell atrophy. J Neuropath. Exp. Neuro!. 24: 653–661.CrossRefGoogle Scholar
  3. 3.
    Nagai, T. McGeer, P., Peng, J., McGeer, E. and Dolman, C. (1983) Choline acetyltransferase immunohistochemistry in brains of Alzheimer’s disease patients and controls. Neurosci. Lett. 36: 195–199.CrossRefGoogle Scholar
  4. 4.
    Pearson, R., Soniew, M., Cuello, A., Powell, T., Eckenstein, F., Esiri, M. and Wilcock, G. (1983) Persistence of cholinergic neurons in the basal nucleus in a brain with senile dementia of the Alzheimer’s type demonstrated by immunohistochemical staining for choline acetyltransferase. Brain Res. 289: 375–379.CrossRefGoogle Scholar
  5. 5.
    Arendt., T., Bigl, V., Tennstedt, A. and Arendt, A. (1985) Neuronal lossin different parts of the nucleus basalis is related to neuritic plaque formation in cortical t’ r get areas in Alzheimer’s disease. Neuroscience 14: 1–14.CrossRefGoogle Scholar
  6. 6.
    Bartus, R., Dean, R., Beer, B. and Lippa, A. (1982) The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417.CrossRefGoogle Scholar
  7. 7.
    Rylett, R., Ball, M and Colhoun, H. (1983) Evidence for high affinity choline transport in synaptosomes prepared from hippocampal and neocortex of patients with Alzheimer’s disease. Brain Res. 289: 169–175.CrossRefGoogle Scholar
  8. 8.
    Collerton, D. (1986) Cholinergic function and intellectual decline in Alzheimer’s disease. Neuroscience 19: 1–28.CrossRefGoogle Scholar
  9. 9.
    Arendash, G., Millard, W., Dunn, A. and Meyer, E. (1987) Long-term neuropathological and neurochemical effects of nucleus basalis lesions in the rat. Science 238: 952–956.CrossRefGoogle Scholar
  10. 10.
    Wenk, G., Cribbs, B. and McCall, L. (1984) Nucleus basalis magnocellularis: optimal coordinates for selective reduction of choline acetyltransferase in frottai neocortex by ibotenic acid injections. Exp. Brain Res. 56: 335–340.CrossRefGoogle Scholar
  11. 11.
    Flicker, C., Dean, L., Watkins, D., Fisher, S. and Bartus, R. (1983) Behavioral and neurochemical effects following neurotoxic lesions of a major cholinergic input to the cerebral cortex in the rat. Pharmacol. Biochem. Behay. 18: 973–981.CrossRefGoogle Scholar
  12. 12.
    Dubois, B., Mayo, W., Agid, Y., LeMoal, M. and Simon, H. (1985) Profound disturbances of spontaneous and learned behaviors following lesion of the nucleus basalis magnocellularis in the rat. Brain Res. 338: 249–258.CrossRefGoogle Scholar
  13. 13.
    Hepler, D., Olton, D., Wenk, G. and Coyle, J. (1985) Lesions in nucleus basalis magnocellularis and medial septal area of rats produce qualitatively similar memory impairments. J. Neurosci. 5: 866–873.Google Scholar
  14. 14.
    Arendash, G., Strong, P. and Mouton, P. (1985) Intracerebral transplantation of cholinergic neurons in a new animal model for Alzheimer’s disease. In: Senile Dementia of the Alzheimer Type (eds: Hutton, J. and Kenny, A.) Alan R. Liss, Inc., New York, pp. 351–376.Google Scholar
  15. 15:.
    Bartus, R., Flicker, C., Dean, R., Pontecorvo, M., Figueiredo, J. and Fisher, S. (1985) Selective memory loss following nucleus basalis lesions: long-term behavioral recovery despite persistent cholinergic deficiencies. Pharm. Biochem. Behay. 23: 125135.Google Scholar
  16. 16.
    Wenk, G., Hughey, D., Boundy, V. and Kim, A. (1987) Neurotransmitters and memory: role of cholinergic, serotonergic, and noradrenergic systems. Behay. Neurosci. 101: 325; 332.Google Scholar
  17. 17.
    Arendash, G., Millard, W., Dawson, R., Dunn, A. and Meyer, E. (1989) Different long-term effects of bilateral and unilateral nucleus basalis lesions on rat cerebral cortical neurotransmitter content. Submitted for publication.Google Scholar
  18. 18.
    Mesulam, M. M., Mufson, E., Wainer, B. and Levey, A (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Chl-Ch6). Neuroscience 11: 1185–1201.CrossRefGoogle Scholar
  19. 19.
    LoConte, G., Casamenti, F., Bigl, V., Milaneschi, E. and Pepeu, G. (1982) Effects of magnocellular forebrain nuclei lesions on acetylcholine output from the cerebral cortex, electrocortigram and behavior. Arch. Ital Biol 120: 176–188.Google Scholar
  20. 20.
    Kryjevic, K, Pumain, R. and Renaud, L (1971) The mechanism of excitation by acetylcholine in the cerebral cortex. J. Physiol. (London) 215: 247–268.Google Scholar
  21. 21.
    Cole, A and Nicoll, R. (1984) Characterization of a slow cholinergic postsynaptic potential recorded in vitro from rat hippocampal pyramidal cells. J. Physiol. (London) 352: 173–188.Google Scholar
  22. 22.
    Agoston, D., Borroni, E. and Richardson, P. (1988) Cholinergic surface antigen chol1 is present in a subclass of VIP containing rat cortical synaptosomes. J. Neurochem. 50: 1659: 1662.Google Scholar
  23. 23.
    Hyman, B., Van Hoesen, G., Damasio, A. and Barnes, C. (1984) Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science 225: 116811270.Google Scholar
  24. 24.
    Coyle, J., Price, D. and DeLong, M. (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219: 1184–1190.CrossRefGoogle Scholar
  25. 25.
    Neary, D., Snowden, J., Bowen, D., Sims, N., Mann, D., Northen, B., Yates, P. and Davison, A. (1986) Alzheimer’s disease: a correlative study. J. Neurol. Neurosurg. Psychiat. 49: 229–237.CrossRefGoogle Scholar
  26. 26.
    Perry, E., Blessed, G., Tomlinson, B., Perry, R., Crow, T., Cross, A., Dockray, G., Dimeline, R. and Arregui, A. (1981) Neurochemical activity in human temporal lobe related to aging and Alzheimer-type changes. Neurobiol. Aging 4: 251–256.CrossRefGoogle Scholar
  27. 27.
    Bowen, D., Smith, C., White, P. and Davison, A. (1976) Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99: 459–496.CrossRefGoogle Scholar
  28. 28.
    Davies, P. (1979) Neurotransmitter-related enzymes in senile dementia of the Alzheimer type. Brain Res. 171: 319–327.CrossRefGoogle Scholar
  29. 29.
    Bowen, D., Sims, M., Benton, J., Curzon, G., Neary, D., Thomas, D. and Davison, A. (1981) Treatment of Alzheimer’s disease: a cautionary note. N. Engl. J. Med. 305: 1016–1019Google Scholar
  30. 30.
    Davies, P., Katzman, R. and Terry, R. (1980) Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer’s disease and Alzheimer senile dementia. Nature 288: 279–280.CrossRefGoogle Scholar
  31. 31.
    Rossor, M., Emson, P., Mountjoy, C. et al. (1980) Reduced amounts of immunoreactive somatostatin in the temporal cortex in senile dementia of Alzheimer type. Neurosci. Lett. 20: 373–377.CrossRefGoogle Scholar
  32. 32.
    Beal, M., Mazurek, M., Chattha, G., Svendsen, C., Bird, E. and Martin, J. (1986) Neuropeptide Y immunoreactivity is reduce in cerebral cortex in Alzheimer’s disease. Ann. Neurol. 20: 282–288.CrossRefGoogle Scholar
  33. 33.
    DeSouza, E. (1988) CRH defects in Alzheimer’s and other neurological diseases. Hosp. Practice 23: 59–71.Google Scholar
  34. 34.
    DeSouza, E., Whitehouse, P., Kuhar, M. Price, D. and Vale, W. (1986) Reciprocal changes m corticotropin-releasing factor (CRF)–like immunoreactivity and CRF receptors in the cerebral cortex of Alzheimer’s disease. Nature 319: 593–595.Google Scholar
  35. 35.
    Chronwall, B., Chase, T. and O’Donohue, T. (1984) Coexistence of neuropeptide Y and somatostatin in rat and human cortical and rat hypothalamus neurons. Neurosci. Lett. 52: 213–217.CrossRefGoogle Scholar
  36. 36.
    Vincent, S., Johansson, D. and Hokfelt, T. (1982) Neuropeptide coexistence in human cortical neurons. Nature 298: 65–67.CrossRefGoogle Scholar
  37. 37.
    Dawbarn, D., Rossor, M., Mountjoy, C., Roth, M. and Emson, P. (1986) Decreased somatostatin immunoreactivity but not neuropeptide Y immunoreactivity in cerebral cortex in senile dementia of Alzheimer type. Neurosci. Lett. 70: 154–159.CrossRefGoogle Scholar
  38. 38.
    Francis, P. and Bowen, D. (1985) Relevance of reduced concentrations of somatostatin in Alzheimer’s disease. Biochem. Society Transactions 13: 170–171.Google Scholar
  39. 39.
    McKinney, M., Davies, P. and Coyle, J., (1982) Somatostatin is not co-localized in cholinergic neurons innervating the rat cerebral cortex-hippocampal functions. Brain Res. 243: 169–172.CrossRefGoogle Scholar
  40. 40.
    Montminy, M. and Bilezikjian, L. (1987) Binding of a nuclear protein to the cyclic AMP response element of the somatostatin gene. Nature 328: 175–178.CrossRefGoogle Scholar
  41. 41.
    Olianas, M., Onali, P. Neff, N. and Costa, E. (1983) Adenylate cyclase activity of synaptic membranes from rat striatum: inhibition by muscarinic agonists. Mol. Ph arm acol. 23: 393–398.Google Scholar
  42. 42.
    Robbins, R., Sutton, R. and Reichlin, S. (1982) Effects of neurotransmitter and cyclic AMP on somatostatin release from cultured cerebral cortical cells. Brain Res. 234: 377–386.Google Scholar
  43. 43.
    Fagg, G. and Foster, A. (1983) Amino acid neurotransmitters and their pathways in the mammalian central nervous system. Neuroscience 9: 701–719.CrossRefGoogle Scholar
  44. 44.
    Meyer, E. St. Onge, E. and Crews, F. (1984) Effects of aging on rat cortical presynaptic cholinergic processes. Neurobioloy of Aging 5: 315–317.CrossRefGoogle Scholar
  45. 45.
    Pedata, R. Slavikova, J. Kotas, A. and Pepeu, G. (1983) Acetylcholine release from rat cortical slices during postnatal development and aging. Neurobiology of Aging 4: 31–35.Google Scholar
  46. 46.
    Hornberger, J., Buell, S., Flood, D., NcNeill, T. and Coleman, P. (1985) Stability of numbers but not size of mouse forebrain cholinergic neurons to 53 months. Neurobiology of Aging 6: 269–275.CrossRefGoogle Scholar
  47. 47.
    Armstrong, D., Buzaki, G., Chen, K, Ruiz, R., Sheffield, R. and F. Gage (1987) Cholinergic neurotransmission in the aged rat: a behavioral, electrophysiological, and anatomical study. Soc. Neuroscience Abstr. 13: 434.Google Scholar
  48. 48.
    Landfield, P. Rose, G., Sandles, L., Wohlstadter, T. and Lynch, G. (1977) Patterns of astroglial hypertrophy and neuronal degeneration in the hippocampus of aged, memory-deficient rats. Journal of Gerontology 32: 3 /12.Google Scholar
  49. 49.
    Sabel, B. and Stein, D. (1981) Extensive loss of subcortical neurons in the aging rat brain. Experimental Neurology 73: 507–516.CrossRefGoogle Scholar
  50. 50.
    Peng, M. and Lee, L. (1979) regional differences of neuron loss of rat brain in old age. Gerontology 25: 205–211.Google Scholar
  51. 51.
    Peters, A., Feldman, M. and Vaughan, D. (1983) The effect of aging on the neuronal population within area 17 of adult rat cerebral cortex. Neurobiology of Aging 4: 273282.Google Scholar
  52. 52.
    Freund, G. (1980) Cholinergic receptor loss in brains of aging mice. Life Sciences 26: 371–375.CrossRefGoogle Scholar
  53. 53.
    Gallagher, M. and Pelleymounter, M. (1988) Spatial learning deficits in old rats: a model for memoly decline in the aged. Neurobiology of Aging 9: 549–556.CrossRefGoogle Scholar
  54. 54.
    Pontecorvo, M., Clissold, D. and Conti, L (1988) Age-related cognitive impairments as assessed with an automated repeated measures memory task: implications for the possible role of acetylcholine and norepinephrine in memory dysfunction. Neurobiology of Aging 9: 617–625.CrossRefGoogle Scholar
  55. 55.
    Barnes, C., Nadel, L. and Honig, W. (1980) Spatial memory deficit in senescent rats. Canadian Journal of Psychology 34: 29–39.CrossRefGoogle Scholar
  56. 56.
    Van der Staay, R., Raaijmakers, W., Sakkee, A. and Van Bezooijen, C. (1988) Spatial working and reference memory in senescent rats after thiopental anaesthesia. Neurosci. Res. Comm. 3: 55–61.Google Scholar
  57. 57.
    Ingram, D. (1988) Complex maze learning in rodents as a model of age-relatedmemory impairment. Neurobiology of Aging 9: 475–485.CrossRefGoogle Scholar
  58. 58.
    Gold, R., McGaugh, J., Hankins, L. Rose, R. and Vasquez, B. (1981) Age dependent changes in retention in rats. Experim. Aging Res. 8: 53–58.Google Scholar
  59. 59.
    Zornetzer, S. Thompson, R. and Rogers, J. (1982) Rapid forgetting in aged rats. Behavioral and Neural Biology 36: 49–60.CrossRefGoogle Scholar
  60. 60.
    Goodrick, C. (1972) Learning by mature-young and aged wistar albino rats as a function of test complexity. J. of Gerontology 27: 353–357.Google Scholar
  61. 61.
    Wallace, J., Krauter, E. and Campbell, B. (1980) Animal models of declining memory in the aged: short-term and spatial memory in the aged rat. J. of Gerontology 35: 355–363.Google Scholar
  62. 62.
    Mouton, P., Meyer, E., Dunn, A., Millard, W. and Arendash, G. (1988) Induction of cortical cholinergic hypofunction and memory retention deficits through intracortical AF64A infusions. Brain Res. 444: 104–118.CrossRefGoogle Scholar
  63. 63.
    Mouton, P., Meyer, E. and Arendash, G. (1989) Intracortical AF64A: memory impairments and recovery from cholinergic hypofunction. Pharm. Biochem. Behay. 32: in press.Google Scholar
  64. 64.
    Palmer, A., Wilcock, G., Esiri, M., Francis, P. and Bowen, D. (1987) Monoaminergic innervation of the frontal and temportal lobes in Alzheimer’s disease. Brain Res. 401: 231–238.CrossRefGoogle Scholar
  65. 65.
    Gottfries, C., Adolfsson, R., Awquilonius, S., Carlsson, A., Eckernas, S., Nordberg, A. Oreland, L, Svennerholm, L., Wilberg, A. and Winblad, B. (1983) Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT). Neurobiology of Aging 3: 261–271.Google Scholar
  66. 66.
    Brenneman, D. Eiden, L. (1986) Vasoactive intestinal peptide and electrical activity influence neuronal survival. Proc. Natl. Acad. Sci. 83: 1159–1162.Google Scholar
  67. 67.
    Brenneman, D., Eiden, L and Siegel, R. (1985) Neurotrophic action of VIP on spinal cord cultures. Peptides 6: 35–39.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Gary W. Arendash
    • 1
  • Gregory J. Sengstock
    • 1
  • Gerry Shaw
    • 2
  • William J. Millard
  1. 1.Department of BiologyUniversity of South FloridaTampaUSA
  2. 2.Department of PharmacodynamicsUniversity of FloridaGainesvilleUSA

Personalised recommendations