Abstract
Alzheimer’s disease (AD) is characterized by degeneration of neurons in several neurotransmitter-specific systems (Price et al., in press; Whitehouse et al., in press b). Alterations in telencephalic presynaptic cholinergic markers, such as choline acetyltransferase (ChAT), have been most closely linked to the severity of clinically apparent dementia and to the density of senile plaques and neurofibrillary tangles (Blessed et al., 1968; Wilcock et al., 1982). The anatomical basis for the presynaptic cholinergic dysfunction in amygdala, hippocampus, and neocortex appears to be loss of neurons in the basal forebrain cholinergic system (Chl-4 system) (Whitehouse et al., 1981; Whitehouse et al., 1982; Arendt et al., 1983; Candy et al., 1983; Tagliavini and Pilleri, 1983). This system is composed of neurons in the medial septum (Chi), diagonal band of Broca (Ch2), and the nucleus basalis of Meynert (nbM) (Ch4) (Hedreen et al., 1983; Mesulam et al., 1983). A role for acetylcholine in dementia is supported by animal experiments in which anticholinergic drugs and anatomical lesions of the Chl-4 system have been shown to produce memory dysfunction (Deutsch, 1971; Aigner et al-, 1984; Olton et al., 1984), In this paper, I will review: our recent clinical studies of neuronal loss in this system in AD and related disorders; evidence for neuronal loss in other neural systems; studies of neurotransmitter receptor alterations in AD; and recent characterizations of cholinergic receptor alterations.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Aigner, T., Mitchell, S., Aggleton, J., DeLortg, M., Struble, R., Price, D., and Mishkin, M., 1984, Effects of scopolamine and physostigmine on recognition memory in monkeys after ibotenic acid injections into the area of the nucleus basalis of Meynert, in: “Alzheimer’s Disease: Advances in Basic Research and Therapies. Proceedings of the Third Meeting of the International Study Group on the Treatment of Memory Disorders Associated with Aging,” R. J. Wurtman, S. H. Corkin, and J. H. Growdon, eds., Zurich, p. 429.
Arertdt, T., Bigl, V., Arendt, A., and Tennstedt, A., 1983, Loss of neurons in the nucleus basalis of Meynert in Alzheimer’s disease, paralysis agitans, arid Korsakoff’s disease, Acta Neuropathol, 61: 101–108.
Ball, M. J., 1977, Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia. A qualitative study, Acta Neuropathol., 37: 111–118.
Blessed, G., Tomlinson, B. E., and Roth, M., 1968, The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects, Br. J. Psychiatry, 114: 797–811.
Bondareff, W., Mountjoy, C. Q., and Roth, M., 1982, Loss of neurons or origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia, Neurology, 32: 164–168.
Bowen, D. M., and Davison, A. N., 1978, Changes in brain lysosomal activity, neurotransmitter-related enzymes, and other proteins in senile dementia, in: “Alzheimer’s Disease: Senile Dementia and Related Disorders” (Aging, Vol. 7), R. Katzman, R. D. Terry, and K. L. Bick, eds., Raven Press, New York, pp. 421–424.
Bowen, D. M., Allen, S. J., Berttori, J. S., Goodhardt, M. J., Haan, E. A., Palmer, A. M., Sims, N. R., Smith, C. C. T., Spillane, J. A., Esiri, M. M., Neary, D., Sriowdori, J. S., Wilcock, G. K., and Davison, A. N., 1983a, Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy iri Alzheimer’s disease, J. Neurochem., 41: 266–272.
Bowen, D. M., Davison, A. N., Arid Sims, N. R., 1983b, The cholinergic system in the ageing brain and dementia, in: “Aging of the Brain” (Aging, Vol. 22), D. Samuel, S. Algeri, S. Gershon, V. E. Grimm, and G. Toffano, eds., Raven Press, New York, pp. 183–190.
Bowen, D. M., Flack, R. H. A., White, P., Smith, C. B., and Davison, A. N., 1974, Brain-decarboxylase activities as indices of pathological change in senile dementia, Lancet,:1247–1249.
Bowen, D. M., Spillane, J. A., Curzon, G., Meier-Ruge, W., White, P., Goodhardt, M. J., Iwangoff, P., and Davison, A. N., 1979, Accelerated ageing or selective neuronal loss as an important cause of dementia?, Lancet 1: 11–14.
Candy, J. M., Perry, R. H., Perry, E. K., Irving, D., Blessed, G., Fairbairn, A. F., and Tomlinson, B. E., 1983, Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases, J. Neurol. Sci., 59: 277–289.
Candy, J. M., Perry, R. H., Perry, E. K., Irving, D., Blessed, G., Fairbairn, A. F., and Tomlinson, B. E., 1983, Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases, J. Neurol. Sci., 59: 277–289.
Candy, J. M., Perry, R. H., Perry, E. K., Irving, D., Blessed, G., Fairbairn, A. F., and Tomlinson, B. E., 1983, Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases, J. Neurol. Sci., 59: 277–289.
Caulfield, M. P., Higgins, G. A., and Straughan, D. W., 1983, Central administration of the muscarinic receptor subtype — selective antagonist pirenzepine selectively impairs passive avoidance learning in the mouse, J Pharm. Pharmacol., 35: 131–132.
Clark, A. W., Lehmann, J., Whitehouse, P. J., Struble, R. G., Coyle, J. T., and Price, D. L., 1983a, Cortico-striato-spinal degeneration (CSSD) mimicking Alzheimer’s disease (AD): studies of the nucleus basalis of Meynert (nbM) and cortical choline acetyltransferase (CAT), J Neuropathol. Exp. Neurol., 42: 334.
Clark, A. W., Parhad, I. M., Folstein, S. E., Whitehouse, P. J., Hedreen, J. C., Price, D. L., and Chase, G. A., 1983b, The nucleus basalis in Huntington’s disease, Neurology, 33: 1262–1267.
Colon, E. J., 1973, The cerebral cortex in presenil dementia. A quantitative analysis, Acta Neuropathol., 23: 281–290.
Corsellis, J. A. N., 1978, Posttraumatic dementia, in: “Alzheimer’s Disease: Senile Dementia and Related Disorders” (Aging, Vol. 7), R. Katzman, R. D. Terry, and K. L. Bick, eds., Raven Press, New York, pp. 125–133.
Cross, A. J., Crow, T. J., Ferrier, I. N., Johnson, J. A., Bloom, S. R., and Corsellis, J. A. N., 1984a, Serotonin receptor changes in dementia of the Alzheimer type, J Neurochem., 43: 1574–1581.
Cross, A. J., Crow, T. J., Johnson, J. A., Perry, E. K., Perry, R. H., Blessed, G., and Tomlirison, B. E., 1984b, Studies on neurotransmitter receptor systems in neocortex and hippocampus in senile dementia of the Alzheimer-type, J Neurol. Sci., 64: 109–117.
Curcio, C. A., and Kemper, T., 1984, Nucleus raphe dorsalis in dementia of the Alzheimer type: neurofibrillary changes and neuronal packing density, J Neuropathol. Exp. Neurol., 43: 359–368.
Davies, P., and Feisullin, S., 1981, Postmortem stability of alpha-bungarotoxin binding sites in mouse and human brain, Brain Res., 216: 449–454.
Davies, P., and Verth, A. H., 1978, Regional distribution of muscarinic acetylcholine receptor in normal and Alzheimer’s-type dementia brains, Brain Res., 138: 385–392.
Deutsch, J. A., 1971, The cholinergic synapse and the site of memory, Science, 174: 788–794.
Forno, L. S., 1978, The locus caeruleus in Alzheimer’s disease, J. Neuropathol. Exp. Neurol., 37: 614.
Hammer, R., Berrie, C. P., Birdsall, N. J. M., Burgen, A. S. V., and Hulme, E. C., 1980, Pirenzepine distinguishes between different subclasses of muscarinic receptors, Nature, 283: 90–92.
Hedreen, J. C., Bacon, S. J., Cork, L. C., Kitt, C. A., Crawford, G. D., Salvaterra, P. M., and Price, D. L., 1983, Immunocytochemical identification of cholinergic neurons in the monkey central nervous system using monoclonal antibodies against choline acetyltransferase, Neurosci. Lett., 43: 173–177.
Herzog, A. G., and Kemper, T. L., 1980, Amygdaloid changes in aging and dementia, Arch. Neurol., 37: 625–629.
Hirano, A., and Zimmerman, H. M., 1962, Alzheimer’s neurofibrillary changes. A topographic study, Arch. Neurol., 7: 227–242.
Hooper, M. W., and Vogel, F. S., 1976, The limbic system in Alzheimer’s disease. A neuropathologic investigation, Am. J. Pathol., 85: 1–20.
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.
Ishii, T., 1966, Distribution of Alzheimer’s neurofibrillary changes in the brain stem and hypothalamus of senile dementia, Acta Neuropathol., 6: 181–187.
Kitt, C. A., Mobley, W. C., Struble, R. G., Cork, L. C., Hedreen, J. C., Wainer, B. H., and Price, D. L., 1984a, Evidence for cholinergic processes in neuritic plaques of aged primates, Neurology, 34: 121.
Kitt, C. A., Price, D. L., Struble, R. G., Cork, L. C., Wainer, B. H., Becher, M. W., and Mobley, W. C., 1984b, Evidence for cholinergic neurites in senile plaques, Science, 226: 1443–1445.
Kuhar, M. J., 1985, Receptor localization with the microscope, in:’Neurotransmitter Receptor Binding’, 2nd edition, H. I. Yamamura, S. J. Enna, and M. J. Kuhar, eds., Raven Press, New York, pp. 153–176.
Lang, W., and Henke, H., 1983, Cholinergic receptor binding and autoradiography in brains of non-neurological and senile dementia of Alzheimer-type patients, Brain Res., 267: 271–280.
Lang, W., and Henke, H., 1983, Cholinergic receptor binding and autoradiography in brains of non-neurological and senile dementia of Alzheimer-type patients, Brain Res., 267: 271–280.
Mash, D. S., and Potter, L. T., 1983, Changes in Ml and M2 muscarine receptors in Alzheimer’s disease and aging, and with lesions of cholinergic neurons in animals, Soc. Neurosci. Abstr., 9: 582.
McKinney, M., and Coyle, J. T., 1982, Regulation of neocortical muscarinic receptors: effects of drug treatment and lesions, J Neurosci., 2: 97–105.
Mesulam, M-M., Mufson, E. J., Levey, A. I., and Wainer, B. H., 1983, Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey, J Comp. Neurol., 214: 170–197.
Morley, B. J., Kemp, G. E., and Salvaterra, P., 1979, Alpha-bungarotoxin binding sites in the CNS, Life Sci., 24: 859–872.
Nakano, I., and Hirano, A., 1984, Parkinson’s disease: neuron loss in the nucleus basalis without concomitant Alzheimer’s disease, Ann. Neurol., 15: 415 - 418.
Nordberg, A., Larsson, C., Adolfsson, R., Alafuzoff, I., and Winblad, B., 1983, Muscarinic receptor compensation in hippocampus of Alzheimer patients, J Neural Transm., 56: 13–19.
Olton, D. S., Hepler, D., Wenk, G., Lehman, J., and Coyle, J., 1984, Lesions of the nucleus basalis magnocellularis and medial septal area in rats produce similar memory impairments, in, “Alzheimer’s Disease: Advances in Basic Research and Therapies. Proceedings of the Third Meeting of the International Study Group on the Treatment of Memory Disorders Associated with Aging,” R. J. Wurtman, S. H. Corkin, and J. H. Growdon, eds., Zurich, pp. 461.
Perry, E. K., Gibson, P. H., Blessed, G., Perry, R. H., and Tomlinson, B. E., 1977, Neurotransmitter enzyme abnormalities in senile dementia, J. Neurol. Sci., 34: 247–265.
Pilleri, G., 1966, The Kluver-Bucy syndrome in man. A clinico-anatomical contribution to the function of the medial temporal lobe structures, Psychiatr. Neurol., 152: 65–103.
Pilleri, G., 1966, The Kluver-Bucy syndrome in man. A clinico-anatomical contribution to the function of the medial temporal lobe structures, Psychiatr. Neurol., 152: 65–103.
Pilleri, G., 1966, The Kluver-Bucy syndrome in man. A clinico-anatomical contribution to the function of the medial temporal lobe structures, Psychiatr. Neurol., 152: 65–103.
Price, D. L., Whitehouse, P. J., Struble, R. G., Coyle, J. T., Clark, A. W., DeLong, M. R., Cork, L. C., and Hedreen, J. C., 1982, Alzheimer’s disease and Down’s syndrome, Ann. N. Y. Acad. Sci., 396: 145–164.
Reisine, T. D., Yamamura, H. I., Bird, E. D., Spokes, E., and Enna, S. J., 1978, Pre- and postsynaptic neurochemical alterations in Alzheimer’s disease, Brain Res., 159: 477–481.
Rinne, J. 0., Rinne, J. K., Laakso, K., Paijarvi,-.-., and Rinne, U. K.,1984, Reduction in muscarinic receptor binding in limbic areas of Alzheimer brain, J Neurol. Neurosurg. Psychiatry, 47: 651–653.
Schwartz, R. D., Lehmann, J., and Kellar, K. J., 1984, Presynaptic nicotinic cholinergic receptors labeled by [3H]acetylcholine on catecholamine and serotonin axons in brain, J Neurochem., 42: 1495–1498.
Schwartz, R. D., McGee, R., Jr., and Kellar, K. J., 1982, Nicotiniccholinergic receptors labeled by [3H]acetylcholine in rat brain, Mol. Pharmacol., 22: 56–62.
Segal, M., 1978, The acetylcholine receptor in the rat hippocampus: nicotinic, muscarinic or both?, Neuropharmacology, 17: 619–623.
Shefer, V. F., 1972, Absolute number of neurons and thickness of the cerebral cortex during aging, senile and vascular dementia, and Pick’s and Alzheimer’s diseases, Zh. Neuropatol. Psikhiatr., 72: 1024–1029.
Struble, R. G., Cork, L. C., Whitehouse, P. J., and Price, D. L., 1982, Cholinergic innervation in neuritic plaques, Science, 216: 413–415.
Struble, R. G., Kitt, C. A., Walker, L. C., Cork, L. C., and Price, D. L., 1984, Somatostatinergic neurites in senile plaques of aged non-human primates, Brain Res., 324: 394–396.
Tagliavini, F., and Pilleri, G., 1983, Neuronal counts in basal nucleus of Meynert in Alzheimer disease and in simple senile dementia, Lancet, 1: 469–470.
Terry, R. D., Peck, A., DeTeresa, R., Schechter, R., and Horoupian, D. S., 1981, Some morphometric aspects of the brain in senile dementia of the Alzheimer type, Ann. Neurol., 10: 184–192.
Uhl, G. R., Hilt, D. C., Hedreen, J. C., Whitehouse, P. J., and Price, D. L., 1983, Pick’s disease (lobar sclerosis): depletion of neurons in the nucleus basalis of Meynert, Neurology, 33: 1470–1473.
Uhl, G. R., McKinney, M., Hedreen, J. C., White, C. L., III, Coyle, J. T., Whitehouse, P. J., and Price, D. L., 1982, Dementia pugilistica: loss of basal forebrain cholinergic neurons and cortical cholinergic markers, Ann. Neurol., 12: 99.
Unnerstall, J. R., Kuhar, M. J., Niehoff, D. L., and Palacios, J. M., 1981, Benzodiazepine receptors are coupled to a subpopulation of gamma-aminobutyric acid (GABA) receptors: evidence from a quantitative autoradiographic study, J Pharmacol. Exp. Ther. 218: 797–804.
White, P., Goodhardt, M. J., Keet, J. P., Hiley, C. R., Carrasco, L. H., Williams, I. E. I., and Bowen, D. M., 1977, Neocortical cholinergic neurons in elderly people, Lancet, 1: 668–670.
White, P., Goodhardt, M. J., Keet, J. P., Hiley, C. R., Carrasco, L. H., Williams, I. E. I., and Bowen, D. M., 1977, Neocortical cholinergic neurons in elderly people, Lancet, 1: 668–670.
Whitehouse, P. J., Hedreen, J. C., Clark, A. W., Zweig, R. M., Jones, B. E., Terry, R. D., Antuono, P. G., Coyle, J. T., Davies, P. F., and Price, D. L., 1984a, Clinical and neurochemical correlates of neuronal loss in the cholinergic basal forebrain system in Alzheimer’s disease, Soc. Neurosci Abstr., 10: 290.
Whitehouse, P. J., Hedreen, J. C., White, C. L., III, and Price, D. L.,1983a, Basal forebrain neurons in the dementia of Parkinson disease, Ann. Neurol., 13: 243–248.
Whitehouse, P. J., Jones, B. E., Kopajtic, T. A., Price, D. L., and Kuhar, M. J., 1984b, Receptors in the nucleus basalis of primates: an in vitro autoradiographic study, Ann. Neurol., 16: 118.
Whitehouse, P. J., Jones, B. E., Kopajtic, T. A., Price, D. L., and Kuhar, M. J., 1984b, Receptors in the nucleus basalis of primates: an in vitro autoradiographic study, Ann. Neurol., 16: 118.
Whitehouse, P. J., Price, D. L., Clark, A. W., Coyle, J. T., and DeLong, M. R., 1981, Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis, Ann. Neurol., 10: 122–126.
Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., and DeLong, M. R., 1982, Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain, Science, 215: 1237–1239.
Whitehouse, P. J., Rajagopalan, R., Kitt, C. A., Jones, B. E., Niehoff, D. L., Kuhar, M. J., arid Price, D. L., 1984c, Muscarinic cholinergic receptors in the amygdala in Alzheimer’s disease, Neurology, 34: 121.
Whitehouse, P. J., Rajagopalan, R., Kitt, C. A., Jones, B. E., Niehoff, D. L., Kuhar, M. J., and Price, D. L., 1984c, Muscarinic cholinergic receptors in the amygdala in Alzheimer’s disease, Neurology, 34: 121.
Whitehouse, P. J., Rajagopalan, R., Kitt, C. A., Jones, B. E., Niehoff, D. L., Kuhar, M. J., arid Price, D. L., 1984c, Muscarinic cholinergic receptors in the amygdala in Alzheimer’s disease, Neurology, 34: 121.
Whitehouse, P. J., Rajagopalan, R., Kitt, C. A., Jones, B. E., Niehoff, D. L., Kuhar, M. J., and Price, D. L., 1984c, Muscarinic cholinergic receptors in the amygdala in Alzheimer’s disease, Neurology, 34: 121.
Whitehouse, P. J., Wamsley, J. K., Zarbin, M. A., Price, D. L., Tourtellotte, W. W., and Kuhar, M. J., 1983b, Amyotrophic lateral sclerosis: alterations in neurotransmitter receptors, Ann. Neurol., 14: 8–16.
Wilcock, G. K., Esiri, M. M., Bowen, D. M., and Smith, C. C. T., 1982, Alzheimer’s disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities, J Neurol. Sci, 57: 407–417.
Young, W. S., Ill, and Kuhar, M. J., 1979, Autoradiography of opiate and benzodiazepine receptors: in vitro labeling of tissue sections, Fed. Proc., 38: 687.
Zweig, R. M., Whitehouse, P. J., Casanova, M. F., Walker, L. C., Jankel, W. R., and Price, D. L., 1985, Loss of putative cholinergic neurons of the peduriculopontine nucleus in progressive supranuclear palsy. Submitted for presentation at the 1985 meeting of the American Neurologicsal Association.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1986 Plenum Press, New York
About this chapter
Cite this chapter
Whitehouse, P.J. (1986). Neuronal Loss and Neurotransmitter Receptor Alterations in Alzheimer’s Disease. In: Fisher, A., Hanin, I., Lachman, C. (eds) Alzheimer’s and Parkinson’s Disease. Advances in Behavioral Biology, vol 29. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-2179-8_11
Download citation
DOI: https://doi.org/10.1007/978-1-4613-2179-8_11
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4612-9283-8
Online ISBN: 978-1-4613-2179-8
eBook Packages: Springer Book Archive