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International Journal of Alzheimer’s Disease
Volume 2010, Article ID 780102, 24 pages
http://dx.doi.org/10.4061/2010/780102
Research Article

Staging of Alzheimer's Pathology in Triple Transgenic Mice: A Light and Electron Microscopic Analysis

1Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
2Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA

Received 5 February 2010; Accepted 24 May 2010

Academic Editor: Gemma Casadesus

Copyright © 2010 Kwang-Jin Oh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. J. L. Eriksen and C. G. Janus, “Plaques, tangles, and memory loss in mouse models of neurodegeneration,” Behavior Genetics, vol. 37, no. 1, pp. 79–100, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Games, D. Adams, R. Alessandrini et al., “Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein,” Nature, vol. 373, no. 6514, pp. 523–527, 1995. View at Google Scholar · View at Scopus
  3. S. Oddo, A. Caccamo, L. Tran et al., “Temporal profile of amyloid-β (Aβ) oligomerization in an in vivo model of Alzheimer disease: a link between Aβ and tau pathology,” Journal of Biological Chemistry, vol. 281, no. 3, pp. 1599–1604, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. J. Götz, N. Deters, A. Doldissen et al., “A decade of tau transgenic animal models and beyond,” Brain Pathology, vol. 17, no. 1, pp. 91–103, 2007. View at Publisher · View at Google Scholar · View at Scopus
  5. J. Götz, J. R. Streffer, D. David et al., “Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior and therapy,” Molecular Psychiatry, vol. 9, no. 7, pp. 664–683, 2004. View at Google Scholar · View at Scopus
  6. T. L. Spires and B. T. Hyman, “Transgenic models of Alzheimer's disease: learning from animals,” NeuroRx, vol. 2, no. 3, pp. 423–437, 2005. View at Publisher · View at Google Scholar · View at Scopus
  7. B. Allen, E. Ingram, M. Takao et al., “Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301s tau protein,” Journal of Neuroscience, vol. 22, no. 21, pp. 9340–9351, 2002. View at Google Scholar · View at Scopus
  8. J. Götz, F. Chen, R. Barmettler, and R. M. Nitsch, “Tau filament formation in transgenic mice expressing P301L tau,” Journal of Biological Chemistry, vol. 276, no. 1, pp. 529–534, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. J. Lewis, E. McGowan, J. Rockwood et al., “Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L)tau protein,” Nature Genetics, vol. 25, no. 4, pp. 402–405, 2000. View at Publisher · View at Google Scholar · View at Scopus
  10. W.-L. Lin, J. Lewis, S.-H. Yen, M. Hutton, and D. W. Dickson, “Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau,” Journal of Neurocytology, vol. 32, no. 9, pp. 1091–1105, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. L. M. Billings, S. Oddo, K. N. Green, J. L. McGaugh, and F. M. LaFerla, “Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice,” Neuron, vol. 45, no. 5, pp. 675–688, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Oddo, A. Caccamo, M. Kitazawa, B. P. Tseng, and F. M. LaFerla, “Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease,” Neurobiology of Aging, vol. 24, no. 8, pp. 1063–1070, 2003. View at Publisher · View at Google Scholar · View at Scopus
  13. S. Oddo, A. Caccamo, J. D. Shepherd et al., “Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction,” Neuron, vol. 39, no. 3, pp. 409–421, 2003. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Oddo, A. Caccamo, I. F. Smith, K. N. Green, and F. M. LaFerla, “A dynamic relationship between intracellular and extracellular pools of Aβ,” American Journal of Pathology, vol. 168, no. 1, pp. 184–194, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. C. R. Overk, C. M. Kelley, and E. J. Mufson, “Brainstem Alzheimer's-like pathology in the triple transgenic mouse model of Alzheimer's disease,” Neurobiology of Disease, vol. 35, no. 3, pp. 415–425, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Hirata-Fukae, H.-F. Li, H.-S. Hoe et al., “Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model,” Brain Research, vol. 1216, pp. 92–103, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. M. A. Mastrangelo and W. J. Bowers, “Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice,” BMC Neuroscience, vol. 9, article 81, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. C. J. Conti, F. Larcher, J. Chesner, and C. M. Aldaz, “Polyacrylamide gel electrophoresis and immunoblotting of proteins extracted from paraffin-embedded tissue sections,” Journal of Histochemistry and Cytochemistry, vol. 36, no. 5, pp. 547–550, 1988. View at Google Scholar · View at Scopus
  19. E. S. Matsuo, R.-W. Shin, M. L. Billingsley et al., “Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau,” Neuron, vol. 13, no. 4, pp. 989–1002, 1994. View at Publisher · View at Google Scholar · View at Scopus
  20. C. H. Fox, F. B. Johnson, J. Whiting, and P. P. Roller, “Formaldehyde fixation,” Journal of Histochemistry and Cytochemistry, vol. 33, no. 8, pp. 845–853, 1985. View at Google Scholar · View at Scopus
  21. N. J. Pollock and J. G. Wood, “Differential sensitivity of the microtubule-associated protein, tau, in Alzheimer's disease tissue to formalin fixation,” Journal of Histochemistry and Cytochemistry, vol. 36, no. 9, pp. 1117–1121, 1988. View at Google Scholar · View at Scopus
  22. B. M. Riederer, “Antigen preservation tests for immunocytochemical detection of cytoskeletal proteins: influence of aldehyde fixatives,” Journal of Histochemistry and Cytochemistry, vol. 37, no. 5, pp. 675–681, 1989. View at Google Scholar · View at Scopus
  23. B. M. Riederer, R. Porchet, R. A. Marugg, and L. I. Binder, “Solubility of cytoskeletal proteins in immunohistochemistry and the influence of fixation,” Journal of Histochemistry and Cytochemistry, vol. 41, no. 4, pp. 609–616, 1993. View at Google Scholar · View at Scopus
  24. J. Q. Trojanowski, M. A. Obrocka, and V. M.-Y. Lee, “Distribution of neurofilament subunits in neurons and neuronal processes: immunohistochemical studies of bovine cerebellum with subunit-specific monoclonal antibodies,” Journal of Histochemistry and Cytochemistry, vol. 33, no. 6, pp. 557–563, 1985. View at Google Scholar · View at Scopus
  25. J. Q. Trojanowski, T. Schuck, M. L. Schmidt, and V. M.-Y. Lee, “Distribution of tau proteins in the normal human central and peripheral nervous system,” Journal of Histochemistry and Cytochemistry, vol. 37, no. 2, pp. 209–215, 1989. View at Google Scholar · View at Scopus
  26. J. C. Vickers, B. M. Riederer, R. A. Marugg et al., “Alterations in neurofilament protein immunoreactivity in human hippocampal neurons related to normal aging and Alzheimer's disease,” Neuroscience, vol. 62, no. 1, pp. 1–13, 1994. View at Publisher · View at Google Scholar · View at Scopus
  27. M. Goedert, R. Jakes, R. A. Crowther et al., “Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: identification of phosphorylation sites in tau protein,” Biochemical Journal, vol. 301, no. 3, pp. 871–877, 1994. View at Google Scholar · View at Scopus
  28. M. Mercken, M. Vandermeeren, U. Lubke et al., “Monoclonal antibodies with selective specificity for Alzheimer Tau are directed against phosphatase-sensitive epitopes,” Acta Neuropathologica, vol. 84, no. 3, pp. 265–272, 1992. View at Google Scholar · View at Scopus
  29. M. Goedert, R. Jakes, and E. Vanmechelen, “Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205,” Neuroscience Letters, vol. 189, no. 3, pp. 167–169, 1995. View at Publisher · View at Google Scholar · View at Scopus
  30. S. G. Greenberg and P. Davies, “A preparation of Alzheimer paired helical filaments that displays distinct τ proteins by polyacrylamide gel electrophoresis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 15, pp. 5827–5831, 1990. View at Publisher · View at Google Scholar · View at Scopus
  31. E. Lang, G. I. Szendrei, V. M.-Y. Lee, and L. Otvos Jr., “Immunological and conformational characterization of a phosphorylated immunodominant epitope on the paired helical filaments found in Alzheimer's disease,” Biochemical and Biophysical Research Communications, vol. 187, no. 2, pp. 783–790, 1992. View at Publisher · View at Google Scholar · View at Scopus
  32. L. Otvos Jr., L. Feiner, E. Lang, G. I. Szendrei, M. Goedert, and V. M.-Y. Lee, “Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404,” Journal of Neuroscience Research, vol. 39, no. 6, pp. 669–673, 1994. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Carmel, E. M. Mager, L. I. Binder, and J. Kuret, “The structural basis of monoclonal antibody Alz50's selectivity for Alzheimer's disease pathology,” Journal of Biological Chemistry, vol. 271, no. 51, pp. 32789–32795, 1996. View at Publisher · View at Google Scholar · View at Scopus
  34. G. A. Jicha, B. Berenfeld, and P. Davies, “Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer's disease,” Journal of Neuroscience Research, vol. 55, no. 6, pp. 713–723, 1999. View at Publisher · View at Google Scholar · View at Scopus
  35. G. A. Jicha, R. Bowser, I. G. Kazam, and P. Davies, “Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau,” Journal of Neuroscience Research, vol. 48, no. 2, pp. 128–132, 1997. View at Publisher · View at Google Scholar · View at Scopus
  36. B. L. Wolozin, A. Pruchnicki, D. W. Dickson, and P. Davies, “A neuronal antigen in the brains of Alzheimer patients,” Science, vol. 232, no. 4750, pp. 648–650, 1986. View at Google Scholar · View at Scopus
  37. D. B. Rye, J. Leverenz, S. G. Greenberg, P. Davies, and C. B. Saper, “The distribution of Alz-50 immunoreactivity in the normal human brain,” Neuroscience, vol. 56, no. 1, pp. 109–127, 1993. View at Publisher · View at Google Scholar · View at Scopus
  38. S. D. Yan, S. F. Yan, X. Chen et al., “Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide,” Nature Medicine, vol. 1, no. 7, pp. 693–699, 1995. View at Google Scholar · View at Scopus
  39. F. G. De Felice, P. T. Velasco, M. P. Lambert et al., “Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine,” Journal of Biological Chemistry, vol. 282, no. 15, pp. 11590–11601, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. F. G. De Felice, D. Wu, M. P. Lambert et al., “Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers,” Neurobiology of Aging, vol. 29, no. 9, pp. 1334–1347, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. S. T. Ferreira, M. N. N. Vieira, and F. G. De Felice, “Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases,” IUBMB Life, vol. 59, no. 4-5, pp. 332–345, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. C. G. Glabe, “Structural classification of toxic amyloid oligomers,” Journal of Biological Chemistry, vol. 283, no. 44, pp. 29639–29643, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. P. N. Lacor, M. C. Buniel, P. W. Furlow et al., “Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease,” Journal of Neuroscience, vol. 27, no. 4, pp. 796–807, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. M. P. Lambert, P. T. Velasco, L. Chang et al., “Monoclonal antibodies that target pathological assemblies of Aβ,” Journal of Neurochemistry, vol. 100, no. 1, pp. 23–35, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. G. M. Shankar, B. L. Bloodgood, M. Townsend, D. M. Walsh, D. J. Selkoe, and B. L. Sabatini, “Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway,” Journal of Neuroscience, vol. 27, no. 11, pp. 2866–2875, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. D. M. Walsh, D. M. Hartley, M. M. Condron, D. J. Selkoe, and D. B. Teplow, “In vitro studies of amyloid β-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692 → Gly) Alzheimer's disease,” Biochemical Journal, vol. 355, no. 3, pp. 869–877, 2001. View at Google Scholar · View at Scopus
  47. D. M. Walsh and D. J. Selkoe, “Aβ oligomers—a decade of discovery,” Journal of Neurochemistry, vol. 101, no. 5, pp. 1172–1184, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. C. Hirata-Fukae, H.-F. Li, L. Ma et al., “Levels of soluble and insoluble tau reflect overall status of tau phosphorylation in vivo,” Neuroscience Letters, vol. 450, no. 1, pp. 51–55, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. J. C. Carroll, E. R. Rosario, L. Chang et al., “Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice,” Journal of Neuroscience, vol. 27, no. 48, pp. 13357–13365, 2007. View at Publisher · View at Google Scholar · View at Scopus
  50. T. D. Garver, K. A. Harris, R. A. W. Lehman, V. M.-Y. Lee, J. Q. Trojanowski, and M. L. Billingsley, “τ Phosphorylation in human, primate, and rat brain: evidence that a pool of τ is highly phosphorylated in vivo and is rapidly dephosphorylated in vitro,” Journal of Neurochemistry, vol. 63, no. 6, pp. 2279–2287, 1994. View at Google Scholar · View at Scopus
  51. J. Q. Trojanowski and V. M.-Y. Lee, “Phosphorylation of paired helical filament tau in Alzheimer's disease neurofibrillary lesions: focusing on phosphatases,” FASEB Journal, vol. 9, no. 15, pp. 1570–1576, 1995. View at Google Scholar · View at Scopus
  52. Z. Liang, F. Liu, K. Iqbal, I. Grundke-Iqbal, J. Wegiel, and C.-X. Gong, “Decrease of protein phosphatase 2A and its association with accumulation and hyperphosphorylation of tau in Down syndrome,” Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 295–302, 2008. View at Google Scholar · View at Scopus
  53. J.-Z. Wang, I. Grundke-Iqbal, and K. Iqbal, “Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration,” European Journal of Neuroscience, vol. 25, no. 1, pp. 59–68, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. F. Liu, I. Grundke-Iqbal, K. Iqbal, and C.-X. Gong, “Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation,” European Journal of Neuroscience, vol. 22, no. 8, pp. 1942–1950, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Soulié, J. Lépagnol, A. Delacourte, and M. L. Caillet-Boudin, “Dephosphorylation studies of SKNSH-SY 5Y cell Tau proteins by endogenous phosphatase activity,” Neuroscience Letters, vol. 206, no. 2-3, pp. 189–192, 1996. View at Publisher · View at Google Scholar · View at Scopus
  56. P. Lavenex, P. B. Lavenex, J. L. Bennett, and D. G. Amaral, “Postmortem changes in the neuroanatomical characteristics of the primate brain: hippocampal formation,” Journal of Comparative Neurology, vol. 512, no. 1, pp. 27–51, 2009. View at Publisher · View at Google Scholar · View at Scopus
  57. N. Movsesyan, A. Ghochikyan, M. Mkrtichyan et al., “Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine—a novel immunotherapeutic strategy,” PLoS ONE, vol. 3, no. 5, article e2124, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Oddo, L. Billings, J. P. Kesslak, D. H. Cribbs, and F. M. LaFerla, “Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome,” Neuron, vol. 43, no. 3, pp. 321–332, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Lewis, D. W. Dickson, W.-L. Lin et al., “Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP,” Science, vol. 293, no. 5534, pp. 1487–1491, 2001. View at Publisher · View at Google Scholar · View at Scopus
  60. M. Ramsden, L. Kotilinek, C. Forster et al., “Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L),” Journal of Neuroscience, vol. 25, no. 46, pp. 10637–10647, 2005. View at Publisher · View at Google Scholar · View at Scopus
  61. J. C. Augustinack, A. Schneider, E.-M. Mandelkow, and B. T. Hyman, “Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease,” Acta Neuropathologica, vol. 103, no. 1, pp. 26–35, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. L. I. Binder, A. L. Guillozet-Bongaarts, F. Garcia-Sierra, and R. W. Berry, “Tau, tangles, and Alzheimer's disease,” Biochimica et Biophysica Acta, vol. 1739, no. 2, pp. 216–223, 2005. View at Publisher · View at Google Scholar · View at Scopus
  63. J. Luna-Muñoz, L. Chávez-Macías, F. García-Sierra, and R. Mena, “Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 12, no. 4, pp. 365–375, 2007. View at Google Scholar · View at Scopus
  64. J. Luna-Muñoz, F. García-Sierra, V. Falcón, I. Menéndez, L. Chávez-Macías, and R. Mena, “Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 8, no. 1, pp. 29–41, 2005. View at Google Scholar · View at Scopus
  65. A. D. C. Alonso, T. Zaidi, M. Novak, I. Grundke-Iqbal, and K. Iqbal, “Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6923–6928, 2001. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Goedert, “Tau gene mutations and their effects,” Movement Disorders, vol. 20, no. 12, pp. S45–S52, 2005. View at Publisher · View at Google Scholar · View at Scopus
  67. E. Braak, H. Braak, and E.-M. Mandelkow, “A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads,” Acta Neuropathologica, vol. 87, no. 6, pp. 554–567, 1994. View at Publisher · View at Google Scholar · View at Scopus
  68. I. Sassin, C. Schultz, D. R. Thal et al., “Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert,” Acta Neuropathologica, vol. 100, no. 3, pp. 259–269, 2000. View at Google Scholar · View at Scopus
  69. K. Duff, H. Knight, L. M. Refolo et al., “Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes,” Neurobiology of Disease, vol. 7, no. 2, pp. 87–98, 2000. View at Publisher · View at Google Scholar · View at Scopus
  70. S. D. Ginsberg, S. Che, S. E. Counts, and E. J. Mufson, “Shift in the ratio of three-repeat tau and four-repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease,” Journal of Neurochemistry, vol. 96, no. 5, pp. 1401–1408, 2006. View at Publisher · View at Google Scholar · View at Scopus