Neurobiology of Aging
Volume 30, Issue 9 , Pages 1453-1465 , September 2009

In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model

  • Yuanxin Chen

      Affiliations

    • Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, United States
    • Center for Advanced Brain Imaging, Nathan Kline Institute, Orangeburg, NY, United States
    • ,
  • Victor V. Dyakin

      Affiliations

    • Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, United States
    • Center for Advanced Brain Imaging, Nathan Kline Institute, Orangeburg, NY, United States
    • ,
  • Craig A. Branch

      Affiliations

    • Center for Advanced Brain Imaging, Nathan Kline Institute, Orangeburg, NY, United States
    • Departments of Radiology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, United States
    • ,
  • Babak Ardekani

      Affiliations

    • Center for Advanced Brain Imaging, Nathan Kline Institute, Orangeburg, NY, United States
    • ,
  • Dunsheng Yang

      Affiliations

    • Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, United States
    • ,
  • David N. Guilfoyle

      Affiliations

    • Center for Advanced Brain Imaging, Nathan Kline Institute, Orangeburg, NY, United States
    • ,
  • Jesse Peterson

      Affiliations

    • McLean Hospital, Harvard Medical School, Belmont, MA, United States
    • ,
  • Corrinne Peterhoff

      Affiliations

    • Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, United States
    • ,
  • Stephen D. Ginsberg

      Affiliations

    • Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, United States
    • Department of Psychiatry, New York University School of Medicine, New York, NY, United States
    • Department of Physiology & Neuroscience, New York University School of Medicine, New York, NY, United States
    • ,
  • Anne M. Cataldo

      Affiliations

    • McLean Hospital, Harvard Medical School, Belmont, MA, United States
    • Departments of Psychiatry and Neuropathology, Harvard Medical School, Belmont, MA, United States
    • ,
  • Ralph A. Nixon

      Affiliations

    • Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, United States
    • Department of Psychiatry, New York University School of Medicine, New York, NY, United States
    • Department of Cell Biology, New York University School of Medicine, New York, NY, United States
    • Corresponding Author InformationCorresponding author at: Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States. Tel.: +1 845 398 5423; fax: +1 845 398 5422.

Received 3 May 2007 ,Revised 9 November 2007 ,Accepted 16 November 2007.

References 

  1. Antonarakis SE, Lyle R, Chrast R, Scott HS. Differential gene expression studies to explore the molecular pathophysiology of Down syndrome. Brain Res. Brain Res. Rev. 2001;36(2–3):265–274
  2. Antonarakis SE, Lyle R, Dermitzakis ET, Reymond A, Deutsch S. Chromosome 21 and Down syndrome: from genomics to pathophysiology. Nat. Rev. Genet. 2004;5(10):725–738
  3. Apelt J, Kumar A, Schliebs R. Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human beta-amyloid precursor protein. Brain Res. 2002;953(1–2):17–30
  4. Ardekani BA, Guckemus S, Bachman A, Hoptman MJ, Wojtaszek M, Nierenberg J. Quantitative comparison of algorithms for inter-subject registration of 3D volumetric brain MRI scans. J. Neurosci. Methods. 2005;142(1):67–76
  5. Bakshi R, Benedict RH, Bermel RA, Caruthers SD, Puli SR, Tjoa CW, et al. T2 hypointensity in the deep gray matter of patients with multiple sclerosis: a quantitative magnetic resonance imaging study. Arch. Neurol. 2002;59(1):62–68
  6. Bakshi R, Dmochowski J, Shaikh ZA, Jacobs L. Gray matter T2 hypointensity is related to plaques and atrophy in the brains of multiple sclerosis patients. J. Neurol. Sci. 2001;185(1):19–26
  7. Bartus RT. On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp. Neurol. 2000;163(2):495–529
  8. Baxter LL, Moran TH, Richtsmeier JT, Troncoso J, Reeves RH. Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse. Hum. Mol. Genet. 2000;9(2):195–202
  9. Baxter MG, Chiba AA. Cognitive functions of the basal forebrain. Curr. Opin. Neurobiol. 1999;9(2):178–183
  10. Belichenko PV, Masliah E, Kleschevnikov AM, Villar AJ, Epstein CJ, Salehi A, et al. Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. J. Comp. Neurol. 2004;480(3):281–298
  11. Bierer LM, Haroutunian V, Gabriel S, Knott PJ, Carlin LS, Purohit DP, et al. Neurochemical correlates of dementia severity in Alzheimer's disease: relative importance of the cholinergic deficits. J. Neurochem. 1995;64(2):749–760
  12. Bigl V, Woolf NJ, Butcher LL. Cholinergic projections from the basal forebrain to frontal, parietal, temporal, occipital, and cingulate cortices: a combined fluorescent tracer and acetylcholinesterase analysis. Brain Res. Bull. 1982;8(6):727–749
  13. Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H, et al. Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron. 2002;33(5):677–688
  14. Capone GT. Down syndrome: advances in molecular biology and the neurosciences. J. Dev. Behav. Pediatr. 2001;22(1):40–59
  15. Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA. Properties of the endosomal–lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J. Neurosci. 1996;16:186–199
  16. Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, et al. App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of Down syndrome. J. Neurosci. 2003;23(17):6788–6792
  17. Contestabile A, Fila T, Bartesaghi R, Ciani E. Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down's syndrome and related neurodegenerative diseases. J. Neurochem. 2006;97(2):515–526
  18. Cooper JD, Salehi A, Delcroix JD, Howe CL, Belichenko PV, Chua-Couzens J, et al. 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. U.S.A. 2001;98(18):10439–10444
  19. Costa AC, Grybko MJ. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome. Neurosci. Lett. 2005;382(3):317–322
  20. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 1976;2(8000):1403
  21. Davisson MT, Schmidt C, Akeson EC. Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. Prog. Clin. Biol. Res. 1990;360:263–280
  22. Davisson MT, Schmidt C, Reeves RH, Irving NG, Akeson EC, Harris BS, et al. Segmental trisomy as a mouse model for Down syndrome. Prog. Clin. Biol. Res. 1993;384:117–133
  23. Dijkhuizen RM, Ren J, Mandeville JB, Wu O, Ozdag FM, Moskowitz MA, et al. Functional magnetic resonance imaging of reorganization in rat brain after stroke. Proc. Natl. Acad. Sci. U.S.A. 2001;98(22):12766–12771
  24. Eckenstein FP, Baughman RW, Quinn J. An anatomical study of cholinergic innervation in rat cerebral cortex. Neuroscience. 1988;25(2):457–474
  25. Falangola MF, Dyakin VV, Lee SP, Bogart A, Babb JS, Duff K, et al. Quantitative MRI reveals aging-associated T2 changes in mouse models of Alzheimer's disease. NMR Biomed. 2007;20(3):343–351
  26. Ferrer I, Gullotta F. Down's syndrome and Alzheimer's disease: dendritic spine counts in the hippocampus. Acta Neuropathol. (Berl). 1990;79(6):680–685
  27. Ginsberg SD, Martin LJ. Ultrastructural analysis of the progression of neurodegeneration in the septum following fimbria-fornix transection. Neuroscience. 1998;86:1259–1272
  28. Ginsberg SD, Martin LJ. Axonal transection in adult rat brain induces transsynaptic apoptosis and persistent atrophy of target neurons. J. Neurotrauma. 2002;19:99–109
  29. Ginsberg SD, Rothstein JD, Price DL, Martin LJ. Fimbria-fornix transections selectively down-regulate subtypes of glutamate transporter and glutamate receptor proteins in septum and hippocampus. J. Neurochem. 1996;67:1208–1216
  30. Ginsberg SD, Che S, Wuu J, Counts SE, Mufson EJ. Down regulation of trk but not p75 gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease. J. Neurochem. 2006;97(2):475–487
  31. Granholm AC, Sanders LA, Crnic LS. Loss of cholinergic phenotype in basal forebrain coincides with cognitive decline in a mouse model of Down's syndrome. Exp. Neurol. 2000;161(2):647–663
  32. Guilfoyle DN, Dyakin VV, O'Shea J, Pell GS, Helpern JA. Quantitative measurements of proton spin–lattice (T1) and spin–spin (T2) relaxation times in the mouse brain at 7.0T. Magn. Reson. Med. 2003;49(3):576–580
  33. Gyure KA, Durham R, Stewart WF, Smialek JE, Troncoso JC. Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch. Pathol. Lab. Med. 2001;125(4):489–492
  34. Haacke EM, Cheng NY, House MJ, Liu Q, Neelavalli J, Ogg RJ, et al. Imaging iron stores in the brain using magnetic resonance imaging. Magn. Reson. Imaging. 2005;23(1):1–25
  35. Harmon KM, Wellman CL. Differential effects of cholinergic lesions on dendritic spines in frontal cortex of young adult and aging rats. Brain Res. 2003;992(1):60–68
  36. Hebert LE, Beckett LA, Scherr PA, Evans DA. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis. Assoc. Disord. 2001;15(4):169–173
  37. Hefti F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J. Neurosci. 1986;6:2155–2162
  38. Helpern JA, Jensen J, Lee SP, Falangola MF. Quantitative MRI assessment of Alzheimer's disease. J. Mol. Neurosci. 2004;24(1):45–48
  39. Hodgkins PS, Prasher V, Farrar G, Armstrong R, Sturman S, Corbett J, et al. Reduced transferrin binding in Down syndrome: a route to senile plaque formation and dementia. Neuroreport. 1993;5(1):21–24
  40. Holtzman DM, Li YW, DeArmond SJ, McKinley MP, Gage FH, Epstein CJ, et al. Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants. Proc. Natl. Acad. Sci. U.S.A. 1992;89(4):1383–1387
  41. Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, et al. Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome. Proc. Natl. Acad. Sci. U.S.A. 1996;93(23):13333–13338
  42. Howe CL, Mobley WC. Signaling endosome hypothesis: a cellular mechanism for long distance communication. J. Neurobiol. 2004;58(2):207–216
  43. Hunter CL, Bimonte-Nelson HA, Nelson M, Eckman CB, Granholm AC. Behavioral and neurobiological markers of Alzheimer's disease in Ts65Dn mice: effects of estrogen. Neurobiol. Aging. 2004;25(7):873–884
  44. Iwatsubo T, Mann DMA, Odaka A, Suzuki N, Ihara Y. Amyloid-ß protein (Aß) deposition: Aß42(43) precedes Aß40 in Down's syndrome. Ann. Neurol. 1995;37:294–299
  45. Kleschevnikov AM, Belichenko PV, Villar AJ, Epstein CJ, Malenka RC, Mobley WC. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 2004;24(37):8153–8160
  46. Köhler C, Chan-Palay V, Wu J-Y. Septal neurons containing glutamic acid decarboxylase immunoreactivity project to the hippocampal region in the rat brain. Anat. Embryol. 1984;169:41–44
  47. Kromer LF. Nerve growth factor treatment after brain injury prevents neuronal death. Science. 1987;235:214–216
  48. Mattson MP. Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative disorders. Ann. N.Y. Acad. Sci. 2004;1012:37–50
  49. Meshorer E, Biton IE, Ben-Shaul Y, Ben-Ari S, Assaf Y, Soreq H, et al. Chronic cholinergic imbalances promote brain diffusion and transport abnormalities. FASEB J. 2005;19(8):910–922
  50. Mesulam MM, Mufson EJ, Levey AI, Wainer BH. 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. 1983;214(2):170–197
  51. Mesulam MM, Mufson EJ, Wainer BH, Levey AI. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1–Ch6). Neuroscience. 1983;10(4):1185–1201
  52. Mufson EJ, Bothwell M, Hersh LB, Kordower JH. Nerve growth factor receptor immunoreactive profiles in the normal, aged human basal forebrain: colocalization with cholinergic neurons. J. Comp. Neurol. 1989;285(2):196–217
  53. Mufson EJ, Bothwell M, Kordower JH. Loss of nerve growth factor receptor-containing neurons in Alzheimer's disease: a quantitative analysis across subregions of the basal forebrain. Exp. Neurol. 1989;105(3):221–232
  54. Mufson EJ, Ginsberg SD, Ikonomovic MD, DeKosky ST. Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J. Chem. Neuroanat. 2003;26(4):233–242
  55. Mufson EJ, Counts SE, Che S, Ginsberg SD. Neuronal gene expression profiling: uncovering the molecular biology of neurodegenerative disease. Prog. Brain Res. 2006;158(2):197–222
  56. Naumann T, Linke R, Frotscher M. Fine structure of rat septohippocampal neurons. I. Identification of septohippocampal projections neurons by retrograde tracing combined with electron microscopic immunocytochemistry and intracellular staining. J. Comp. Neurol. 1992;325:207–218
  57. Nixon RA. Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol. Aging. 2005;26(3):373–382
  58. Nixon RA, Cataldo AM. Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease. J. Alzheimers Dis. 2006;9(3 Suppl.):277–289
  59. Olson LE, Roper RJ, Baxter LL, Carlson EJ, Epstein CJ, Reeves RH. Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes. Dev. Dyn. 2004;230(3):581–589
  60. Paxinos G, Franklin KBJ. The Mouse Brain in Stereotaxic Coordinates. Second ed.. San Diego: Academic Press; 2001;
  61. Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, et al. Molecular mapping of Alzheimer-type dementia in Down's syndrome. Ann. Neurol. 1998;43(3):380–383
  62. Prasher VP, Gosling P, Blair J. Role of iron in Alzheimer-type dementia in Down syndrome. Int. J. Geriatr. Psychiatry. 1998;13(11):818–819
  63. Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, et al. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat. Genet. 1995;11(2):177–184
  64. Robertson RT, Gallardo KA, Claytor KJ, Ha DH, Ku KH, Yu BP, et al. Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons. Cereb. Cortex. 1998;8(2):142–155
  65. Rovelet-Lecrux A, Hannequin D, Raux G, Meur NL, Laquerriere A, Vital A, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat. Genet. 2006;38(1):24–26
  66. Rovira A, Alonso J, Cucurella G, Nos C, Tintore M, Pedraza S, et al. Evolution of multiple sclerosis lesions on serial contrast-enhanced T1-weighted and magnetization-transfer MR images. AJNR Am. J. Neuroradiol. 1999;20(10):1939–1945
  67. Sago H, Carlson EJ, Smith DJ, Kilbridge J, Rubin EM, Mobley WC, et al. Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. PNAS. 1998;95(11):6256–6261
  68. Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, et al. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006;51(1):29–42
  69. Seo H, Isacson O. Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice. Exp. Neurol. 2005;193(2):469–480
  70. Siarey RJ, Stoll J, Rapoport SI, Galdzicki Z. Altered long-term potentiation in the young and old Ts65Dn mouse, a model for Down Syndrome. Neuropharmacology. 1997;36(11–12):1549–1554
  71. Siarey RJ, Carlson EJ, Epstein CJ, Balbo A, Rapoport SI, Galdzicki Z. Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology. 1999;38(12):1917–1920
  72. Sofroniew MV, Galletly NP, Isacson O, Svendsen CN. Survival of adult basal forebrain cholinergic neurons after loss of target neurons. Science. 1990;247(4940):338–342
  73. Suetsugu M, Mehraein P. Spine distribution along the apical dendrites of the pyramidal neurons in Down's syndrome. A quantitative Golgi study. Acta Neuropathol. (Berl). 1980;50(3):207–210
  74. Swanson LW, Cowan WM. The connections of the septal region in the rat. J. Comp. Neurol. 1979;186(4):621–656
  75. Tuszynski, M.H., Thal, L., Pay, M., Salmon, D.P., U, H.-S., Bakay, R., Patel, P., Blesch, A., Vahlsing, H.L., Ho, G., Tong, G., Potkin, S.G., Fallon, J., Hansen, L., Mufson, E.J., Kordower, J.H., Gall, C., Conner, J.M., 2005. A Phase I clinical trial of nerve growth factor gene therapy for Alzheimer's disease. Nat. Med. 11 (5), 551–555.
  76. Villar AJ, Belichenko PV, Gillespie AM, Kozy HM, Mobley WC, Epstein CJ. Identification and characterization of a new Down syndrome model, Ts[Rb(12.1716)]2Cje, resulting from a spontaneous Robertsonian fusion between T(171)65Dn and mouse chromosome 12. Mamm. Genome. 2005;16(2):79–90
  77. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delong MR. Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. Science. 1982;215(4537):1237–1239
  78. Wisniewski KE, Dalton AJ, Crapper McLachlan DR, Wen GY, Wisniewski HM. Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology. 1985;35(7):957–961
  79. Woolf NJ. Cholinoceptive cells in rat cerebral cortex: somatodendritic immunoreactivity for muscarinic receptor and cytoskeletal proteins. J. Chem. Neuroanat. 1993;6(6):375–390
  80. Zheng F, Khanna S. Selective destruction of medial septal cholinergic neurons attenuates pyramidal cell suppression, but not excitation in dorsal hippocampus field CA1 induced by subcutaneous injection of formalin. Neuroscience. 2001;103(4):985–998

PII: S0197-4580(07)00448-4

doi: 10.1016/j.neurobiolaging.2007.11.026

Neurobiology of Aging
Volume 30, Issue 9 , Pages 1453-1465 , September 2009

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