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Neurochemical Research

, Volume 33, Issue 2, pp 318–327 | Cite as

The Place of Choline Acetyltransferase Activity Measurement in the “Cholinergic Hypothesis” of Neurodegenerative Diseases

  • Antonio ContestabileEmail author
  • Elisabetta Ciani
  • Andrea Contestabile
Original Paper

Abstract

The so-called “cholinergic hypothesis” assumes that degenerative dysfunction of the cholinergic system originating in the basal forebrain and innervating several cortical regions and the hippocampus, is related to memory impairment and neurodegeneration found in several forms of dementia and in brain aging. Biochemical methods measuring the activity of the key enzyme for acetylcholine synthesis, choline acetyltransferase, have been used for many years as a reliable marker of the integrity or the damage of the cholinergic pathways. Stereologic counting of the basal forebrain cholinergic cell bodies, has been additionally used to assess neurodegenerative changes of the forebrain cholinergic system. While initially believed to mark relatively early stages of disease, cholinergic dysfunction is at present considered to occur in advanced dementia of Alzheimer’s type, while its involvement in mild and prodromal stages of the disease has been questioned. The issue is relevant to better understand the neuropathological basis of the diseases, but it is also of primary importance for therapy. During the last few years, indeed, cholinergic replacement therapies, mainly based on the use of acetylcholinesterase inhibitors to increase synaptic availability of acetylcholine, have been exploited on the assumption that they could ameliorate the progression of the dementia from its initial stages. In the present paper, we review data from human studies, as well as from animal models of Alzheimer’s and Down’s diseases, focusing on different ways to evaluate cholinergic dysfunction, also in relation to the time point at which these dysfunctions can be demonstrated, and on some discrepancy arising from the use of different methodological approaches. The reviewed literature, as well as some recent data from our laboratories on a mouse model of Down’s syndrome, stress the importance of performing biochemical evaluation of choline acetyltransferase activity to assess cholinergic dysfunction both in humans and in animal models.

Keywords

Forebrain cholinergic system Alzheimer’s disease Down’s syndrome Animal models Dementia Aging 

References

  1. 1.
    Fonnum F (1975) A rapid radiochemical method for the determination of choline actyltransferase. J Neurochem 24:407–409PubMedGoogle Scholar
  2. 2.
    Eckstein F, Thoenen H (1982) Production of specific antisera and moniclonal antibodies to choline acetyltransferase: characterization and use for identification of cholinergic neurons. EMBO J 1:363–368Google Scholar
  3. 3.
    Armstrong DM, Saper CB, Levey AI et al (1983) Distribution of cholinergic neurons in rat brain: demonstrated by the immunocytochemical localization of choline acetyltransferase. J Comp Neurol 216:53–68PubMedGoogle Scholar
  4. 4.
    Woolf NJ, Eckenstein F, Butcher LL (1984) Cholinergic systems in rat brain: I. projections to the limbic telencephalon. Brain Res Bull 13:751–784PubMedGoogle Scholar
  5. 5.
    Bartus RT, Dean R, Beer B, Lippa A (1982) The cholinergic hypothesis of geriatric memory disfunction. Science 217:408–417PubMedGoogle Scholar
  6. 6.
    Bartus RT (2000) On neurodegenerative diseases, models and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 163:495–529PubMedGoogle Scholar
  7. 7.
    Morris JC (2002) Challenging assumptions about Alzheimer’s disease: mild cognitive impairment and the cholinergic hypothesis. Ann Neurol 51:143–144PubMedGoogle Scholar
  8. 8.
    Sarter M, Bruno JP (2002) Mild cognitive impairment and the cholinergic hypothesis: a very different take on recent data. Ann Neurol 52:384–385PubMedGoogle Scholar
  9. 9.
    Terry AV, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827PubMedGoogle Scholar
  10. 10.
    Buccafusco JJ, Terry AV Jr (2000) Multiple CNS targets for eliciting beneficial effects on memory and cognition. J Pharmacol Exp Ther 295:438–446PubMedGoogle Scholar
  11. 11.
    Davies P, Maloney AJF (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2:1403Google Scholar
  12. 12.
    Perry EK, Gibson PK, Blessed G et al (1977) Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue. J Neurol Sci 34:247–265PubMedGoogle Scholar
  13. 13.
    Whitehouse P, Price DL, Struble RG et al (1982) Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215:1237–1239PubMedGoogle Scholar
  14. 14.
    Davis KL, Mohs RC, Marin D et al (1999) Cholinergic markers in elderly patients with early signs of Alzheimer’s disease. J Am Med Ass 281:1401–1406Google Scholar
  15. 15.
    Tiraboschi P, Hansen LA, Alford M et al (2000) The decline in synapses and cholinergic activity is asynchronous in Alzheimer’s disease. Neurology 55:1278–1283PubMedGoogle Scholar
  16. 16.
    DeKosky ST, Ikonomovic MD, Styren SD et al (2002) Upregulation of choline acetyltransferase activity In hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol 51:145–155PubMedGoogle Scholar
  17. 17.
    Gilmor MI, Erickson JD, Varoqui H et al (1999) Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in elderly with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 411:693–704PubMedGoogle Scholar
  18. 18.
    Mufson EJ, Ma SY, Cochran EJ et al (2000) Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer’s disease. J Comp Neurol 427:19–30PubMedGoogle Scholar
  19. 19.
    Chu Y, Cochran EJ, Bennet DA et al (2001) Downregulation of trkA mRNA within nucleus basalis neurons in individuals with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 443:136–153Google Scholar
  20. 20.
    Mufson EJ, Ma SY, Dills J et al (2002) Loss of basal forebrain P75NTR immunoreactivity in subjects with mild cognitive impairment and Alzheimer’s disease. J Comp Neurol 443:136–153PubMedGoogle Scholar
  21. 21.
    Mufson EJ, Bothwell M, Hersh LB, Kordower JH (1989) Nerve growth factor receptor immunoreactive profiles in the normal, aged human basal forebrain: colocalization with cholinergic neurons. J Comp Neurol 285:196–217PubMedGoogle Scholar
  22. 22.
    Mufson EJ, Ginsberg S, Ikonomovic MD, DeKosky ST (2003) Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26:233–242PubMedGoogle Scholar
  23. 23.
    Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition and treatment strategies. Prog Neurobiol 68:209–245PubMedGoogle Scholar
  24. 24.
    Picciotto MR, Zoli M (2002) Nicotinic recptors in aging and dementia. J Neurobiol 53:641–655PubMedGoogle Scholar
  25. 25.
    Sofroniew MV, Howe CL, Mobley WC (2001) Nerve growth factor signaling, neuroprotection and neural repair. Annu Rev Neurosci 24:1217–1281PubMedGoogle Scholar
  26. 26.
    Mufson EJ, Kroin JS, Sendera TJ, Sobreviela T (1999) Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases. Prog Neurobiol 57:451–484PubMedGoogle Scholar
  27. 27.
    Dai J, Buijs RM, Kamphorst W, Swaab DF (2002) Impaired axonal transport of cortical neurons in Alzheimer’s disease is associated with neuropathological changes. Brain Res 948:138–144PubMedGoogle Scholar
  28. 28.
    Counts SE, Mufson EJ (2005) The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer’s disease. J Neuropath Exp Neurol 64:263–272PubMedGoogle Scholar
  29. 29.
    Ikonomovic MD, Mufson EJ, Wuu J et al (2003) Cholinergic plasticity in hippocampus with mild cognitive impairment: correlation with Alzheimer’s neuropathology. J Alzheimer Dis 5:39–48Google Scholar
  30. 30.
    Gomez-Isla T, Price JL, Mckeel DW Jr et al (1996) Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 16:4491–4500PubMedGoogle Scholar
  31. 31.
    Kordower JH, Chu Y, Stebbins JT et al (2001) Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 49:202–213PubMedGoogle Scholar
  32. 32.
    Allen SJ, MacGowan SH, Tyler S, Wilcock GK et al (1997) Reduced cholinergic function in normal and Alzheimer’s disease brain is associated with apolipoprotein E4 genotype. Neurosci Lett 239:33–36PubMedGoogle Scholar
  33. 33.
    Lai MK, Tsang SW, Garcia-Alloza M, Minger SL (2006) Selective effects of the APOE epsilon4 allele on presynaptic cholinergic markers in the neocortex of Alzheimer’s disease. Neurobiol Dis 22:551–561Google Scholar
  34. 34.
    Corey-Bloom J, Tiraboschi P, Hansen LA, Alford M et al (2000) E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer’s disease. Neurology 54:403–406PubMedGoogle Scholar
  35. 35.
    Tiraboschi P, Hansen LA, Masliah E, Alford M et al (2004) Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer’s disease. Neurology 62:1977–1983PubMedGoogle Scholar
  36. 36.
    Pomara N, Willoughby LM, Wesnes K, Sidtis JJ (2004) Increased anticholinergic challenge-induced memory impairment associated with the APOE-epsilon4 allele in the elderly: a controlled pilot study. Neuropsychopharmacology 28:403–409Google Scholar
  37. 37.
    Wirths O, Multhaup G, Bayer TA (2004) A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide—the first step of a fatal cascade. J Neurochem 91:513–520PubMedGoogle Scholar
  38. 38.
    Cuello CA (2005) Intracellular and extracellular Aβ, a tale of two neuropathologies. Brain Pathol 15:66–71PubMedCrossRefGoogle Scholar
  39. 39.
    Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci 8:1051–1058PubMedGoogle Scholar
  40. 40.
    Tanzi RE (2005) The synaptic Aβ hypothesis of Alzheimer disease. Nature Neurosci 8:977–979PubMedGoogle Scholar
  41. 41.
    Beach TG, Kuo YM, Spiegel K et al (2000) The cholinergic deficit coincides with Abeta deposition at the earliest histopathological stages of Alzheimer disease. J Neuropathol Exp Neurol 59:308–313PubMedGoogle Scholar
  42. 42.
    Jhamandas JK, Cho C, Jassar B et al (2001) Cellular mechanisms for amyloid-β-protein activation of rat cholinergic basal forebrain neurons. J Neurophysiol 86:1312–1320PubMedGoogle Scholar
  43. 43.
    Liu Q-S, Kawai H, Berg DW (2001) β-amyloid peptide blocks the response of α7–containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci USA 98:4734–4739PubMedGoogle Scholar
  44. 44.
    Selkoe DJ (2002) Alzheinmer’s disease is a synaptic failure. Science 298:789–791PubMedGoogle Scholar
  45. 45.
    Auld DS, Kornecook TJ, Bastianetto S, Quirion R (2002) Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol 68:209–245PubMedGoogle Scholar
  46. 46.
    Page KJ, Everitt BJ, Robbins TW et al (1991) Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuron loss. Neuroscience 43:457–472PubMedGoogle Scholar
  47. 47.
    Robbins TW, Everitt BJ, Marston HM et al (1989) Comparative effects of ibotenic acid- and quisqualic acid-induced lesions of the substantia innominata on attentional function in the rat: further implications for the role of the cholinergic neurons of the nucleus basalis in cognitive processes. Behav Brain Res 35:221–240PubMedGoogle Scholar
  48. 48.
    Waite JJ, Chen AD, Wardlow ML et al (1995) 192 immunoglobulin G-saporin produces graded behavioral and biochemical changes accompanying the loss of cholinergic neurons of the basal forebrain and cerebellar Purkinje cells. Neuroscience 65:463–476PubMedGoogle Scholar
  49. 49.
    Schliebs R, Rossner S, Bigl V (1996) Immunolesion by 192IgG-saporin of rat basal forebrain cholinergic system: a useful tool to produce cortical cholinergic dysfunction. Prog Brain Res 109:253–264PubMedCrossRefGoogle Scholar
  50. 50.
    Calzà L, Giuliani A, Fernandez M et al (2003) Neural stem cells and cholinergic neuron: regulation by immunolesion and treatment with mitogens, retinoic acid and nerve growth factor. Proc Natl Acad Sci USA 100:7325–7330PubMedGoogle Scholar
  51. 51.
    Ruberti F, Capsoni S, Comparini A et al (2000) Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen and skeletal muscle distrophy. J Neurosci 20:2581–2601Google Scholar
  52. 52.
    Capsoni S, Ugolini G, Comparini A et al (2000) Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc Natl Acad Sci USA 97:6826–6831PubMedGoogle Scholar
  53. 53.
    Passavento E, Capsoni S, Domenici L, Cattaneo A (2002) Acute cholinergic rescue of synaptic plasticity in the neurodegenerating cortex of anti-nerve-growth-factor mice. Eur J Neurosci 15:1030–1036Google Scholar
  54. 54.
    Van Leuven F (2000) Single and multiple transgenic mice as models for Alzheimer’s disease. Prog Neurobiol 61:306–312Google Scholar
  55. 55.
    Wong PC, Cai H, Borchelt DR, Price DL (2002) Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 5:633–639PubMedGoogle Scholar
  56. 56.
    Borchelt DR, Ratoviski T, van Lare J et al (1997) Accelerated amyloid depositionin the brains of transgenic mice co-expressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945PubMedGoogle Scholar
  57. 57.
    Calhoun ME, Burgermeister P, Phinney AL et al (1999) Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid. Proc Natl Acad Sci USA 96:14088–14093PubMedGoogle Scholar
  58. 58.
    Chen G, Chen KS, Knox J et al (2000) A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 405:975–979Google Scholar
  59. 59.
    Mucke L, Masliah E, Yu GQ et al (2000) High level neuronal expression of Aβ1–42 in wild type human amyloid precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058PubMedGoogle Scholar
  60. 60.
    Oddo B, Caccamo A, Sheperd JD et al (2003) Triple transgenic model of Alzheimer’s disease with plaques And tangles: intracellular Aβ and synaptic dysfunction. Neuron 39:409–421PubMedGoogle Scholar
  61. 61.
    Irizarry MC, Soriano F, McNamara M et al (1997) Aβ deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053–7059PubMedGoogle Scholar
  62. 62.
    Calhoun ME, Wiederhold KH, Abramowski D et al (1998) Neuron loss in APP transgenic mice. Nature 395:755–756PubMedGoogle Scholar
  63. 63.
    Chui DH, Tanahashi H, Ozawa K et al (1999) Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation. Nat Med 5:560–564PubMedGoogle Scholar
  64. 64.
    Takeuchi A, Irizarry MC, Duff K et al (2000) Age-related amyloid β deposition in transgenic mice overexpressing both Alzheimer mutant presenilin1 and amyloid β precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol 157:331–339PubMedGoogle Scholar
  65. 65.
    Urbanc B, Cruz L, Le R et al. (2002) NEurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer’s disease. Proc Natl Acad Sci USA 99:13990–13995PubMedGoogle Scholar
  66. 66.
    Schmitz C, Rutten BPF, Pielen A et al (2004) Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 164:1495–1502PubMedGoogle Scholar
  67. 67.
    Casas C, Sergeant N, Itier J-M et al (2004) Massive CA1/2 neuronal loss with intraneuronal and n-terminal truncated A 42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300PubMedGoogle Scholar
  68. 68.
    Wong TP, Debeir T, Duff K, Cuello AC (1999) Reorganization of cholinergic terminals in the cerebral cortex and hippocampus in transgenic mice carrying mutated presenilin-1 and amyloid precursor protein transgenes. J Neurosci 19:2706–2716PubMedGoogle Scholar
  69. 69.
    Jaffar S, Counts SE, Ma SY et al (2001) Neuropathology of mice carrying mutant APPSWE and/or PS1M146L transgenes: alterations in p75NTR cholinergic basal forebrain septohippocampal pathway. Exp Neurol 170:227–243PubMedGoogle Scholar
  70. 70.
    Hernandez D, Sugaya K, Qu T et al (2001) Survival and plasticity of basal forebrain cholinergic systems in mice transgenic for presenilin-1 and amyloid protein mutant genes. Neuroreport 12:1377–1384PubMedGoogle Scholar
  71. 71.
    German DC, Yazdani U, Speciale SG et al (2003) Cholinergic neuropathology in a mouse model of Alzheimer’s disease. J Comp Neurol 462:371–381PubMedGoogle Scholar
  72. 72.
    Gau JT, Steinhilb ML, D’Amato CJ et al (2002) Stable beta secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice. Am J Pathol 160:731–738PubMedGoogle Scholar
  73. 73.
    Apelt J, Kumar A, Schliebs R (2002) Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swidish mutation of human beya-amyloid precursor protein. Brain Res 953:17–30PubMedGoogle Scholar
  74. 74.
    Luth HJ, Ihunvo AO, Arendt T, schliebs R (2003) Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice. Brain Res 977:16–22PubMedGoogle Scholar
  75. 75.
    Buttini M, Yu GQ, Shockley K et al (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci 22:10539–10548PubMedGoogle Scholar
  76. 76.
    Feng Z, Chang Y, Cheng Y et al (2004) Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer’s disease. J Pineal Res 37:129–136PubMedGoogle Scholar
  77. 77.
    Hartmann J, Erb C, Ebert U et al (2004) Central cholinergic functions in human amyloid precursor protein knock-in/presenilin-1 transgenic mice. Neuroscience 125:1009–1017PubMedGoogle Scholar
  78. 78.
    Van Dam D, Marescau B, Engelborghs et al (2005) Analysis of cholinergic markers, biogenic amines, and amino acids in the CNS of two APP overexpression mouse models. Neurochem Int 46:409–422Google Scholar
  79. 79.
    Hayes A, Batshaw ML (1993) Down syndrome. Pediatr Clin North Am 40:523–529PubMedGoogle Scholar
  80. 80.
    Wisniewski KE, Wisniewski HM, Wen GY (1985) Occurrence of neuropathological changes and dementia in Alzheimer’s disease and Down’s syndrome. Ann Neurol 17:278–282PubMedGoogle Scholar
  81. 81.
    Mann DM, Esiri MM (1989) The pattern of acquisition of plaques and tangles in the brain of patients under 50 years of age with Down’s syndrome. J Neurol Sci 89:169–179PubMedGoogle Scholar
  82. 82.
    Casanova MF, Walker LC, Whitehous PJ, Price DL (1985) Abnormalities of the nucleus basalis In Down’s syndrome. Ann Neurol 18:310–313PubMedGoogle Scholar
  83. 83.
    Goodrige H, Reynolds GP, Czudek C et al (1987) Alzheimer-like neurotransmitter deficits in adult Down’s syndrome brain tissue. J Neurol Neurosur Psychyat 50:775–778CrossRefGoogle Scholar
  84. 84.
    Fodale V, Mafrica F, Caminiti V, Grasso G (2006) The cholinergic system in Down’s syndrome. J Intellect Disabil 10:261–274PubMedGoogle Scholar
  85. 85.
    Kish S, Karlinsky H, Becker L et al (1989) Down’s syndrome individuals begin life with normal levels of brain cholinergic markers. J Neurochem 52:1183–1187PubMedGoogle Scholar
  86. 86.
    Korenberg JR, Chen XN, Schipper R et al (1994) Down syndrome phenotypes: the consequence of chromosomal imbalance. Proc Natl Acad Sci USA 91:4997–4501PubMedGoogle Scholar
  87. 87.
    Coyle JT, Oster-Granite ML, Reeves MH, Gearhart JD (1988) Down syndrome, Alzheimer’s disease and the trisomy 16 mouse. Trends Neurosci 11:390–394PubMedGoogle Scholar
  88. 88.
    Holtzman DM, Kilbridge J, Chen KS et al (1995) Preliminary characterization of the central nervous system in partial trisomy 16 mice. Prog Clin Biol Res 393:227–240PubMedGoogle Scholar
  89. 89.
    Flieder JL, Epstein CJ, Rapoport SI et al (1994) Regional alterations of cholinergic function in central neurons of trisomy 16 mouse fetuses, an animal model of human trisomy 21 (Down syndrome). Brain Res 658:27–32CrossRefGoogle Scholar
  90. 90.
    Nelson PG, Fitzgerald S, Rapoport SI et al (1997) Cerebral cortical astroglia from the trisomy 16 mouse, a model for Down syndrome, produce neuronal cholinergic deficit in cell culture. Proc Natl Acad Sci USA 94:12644–12648PubMedGoogle Scholar
  91. 91.
    Allen DD, Martin J, Arriagada C et al (2000) Impaired cholinergic function in cell lines derived for the cerebral cortex of normal and trisomy 16 mice. Eur J Neurosci 12:3259–3264PubMedGoogle Scholar
  92. 92.
    Cardenas AM, Arriagada C, Allen DD et al (2002) Cell lines derived from hippocampal neurons of the normal and trisomy 16 mouse fetus (a model for Down syndrome) exhibit neuronal markers, cholinergic function and functional neurotransmitter receptors. Exp Neurol 177:159–170PubMedGoogle Scholar
  93. 93.
    Davisson MT, Schmidt C, Akeson EC (1990) Segmental trisomy of murine chromosome 16: a new model for studying Down syndrome. Prog Clin Biol Res 360:263–280PubMedGoogle Scholar
  94. 94.
    Escorihuela RM, Fernandez-Teruel A, Vallina IF et al (1995) A behavioral assessement of Ts65Dn mice: aputative Down’s syndrome model. Neurosci Lett 247:171–174Google Scholar
  95. 95.
    Reeves RH, Irving NJ, Moran TH et al (1995) A mouse model of Down syndrome exhibits learning and behavior deficits. Nature Gen 11:177–184Google Scholar
  96. 96.
    Holtzman DM, Santucci D, Kilbridge J et al (1996) Developmental abnormalities and age-related neurodegenerationin a mouse model of Down syndrome. Proc Natl Acad Sci USA 93:13333–13338PubMedGoogle Scholar
  97. 97.
    Granholm AC, Sanders LA, Crnic LS (2000) Loss of cholinergic phenotype in basal forebrain coincides with cognitive declinein a mouse model of Down’s syndrome. Exp Neurol 161:647–663PubMedGoogle Scholar
  98. 98.
    Hunter CL, Bimonte HA, Granholm AC (2003) Behavioral comparison of 4 and 6 month-old Ts65Dn mice: age-related impairments in working and reference memory. Behav Brain Res 138:121–131PubMedGoogle Scholar
  99. 99.
    Seo H, Isacson O (2005) Abnormal APP, cholinergic and cognitive function in Ts65Dn Down’s model mice. Exp Neurol 193:469–480PubMedGoogle Scholar
  100. 100.
    Cooper JD, Salehi A, Delcroix J-D et al (2001) Failed retrograde transport of NGF In a mouse model of Down’s syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc Natl Acad Sci USA 98:10439–10444PubMedGoogle Scholar
  101. 101.
    Contestabile A, Fila T, Bartesaghi R et al (2006) Choline acetyltransferase activity at different ages in brain Ts65Dn mice, an animal model for Down’s syndrome and related neurodegenerative diseases. J Neurochem 97:515–526PubMedGoogle Scholar
  102. 102.
    Sunderland T, Esposito G, Molchan SE et al (1995) Differential cholinergic regulation in Alzheimer’s patients compared to controls following chronic blockade with scopolamine: a SPECT study. Psychopharmacology 121:231–241PubMedGoogle Scholar
  103. 103.
    Kleschevnikov AM, Belichenko PV, Villar AJ et al (2004) Hippocampal long term potentiation suppressed by increased inhibition in the Ts65Dn mouse model of Down’s syndrome. J Neurosci 24:8153–8160PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Antonio Contestabile
    • 1
    Email author
  • Elisabetta Ciani
    • 2
  • Andrea Contestabile
    • 2
  1. 1.Department of BiologyUniversity of BolognaBolognaItaly
  2. 2.Department of Human and General PhysiologyUniversity of BolognaBolognaItaly

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