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The benefits and limitations of animal models for translational research in neurodegenerative diseases

Nature Medicine volume 16, pages 1210–1214 (2010)Cite this article

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Abstract

Age-related neurodegenerative diseases are largely limited to humans and rarely occur spontaneously in animals. Genetically engineered mouse models recapitulate aspects of the corresponding human diseases and are instrumental in studying disease mechanisms and testing therapeutic strategies. If considered within the range of their validity, mouse models have been predictive of clinical outcome. Translational failure is less the result of the incomplete nature of the models than of inadequate preclinical studies and misinterpretation of the models. This commentary summarizes current models and highlights key questions we should be asking about animal models, as well as questions that cannot be answered with the current models.

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Figure 1: Studies from PubMed were retrieved using the keywords 'mouse', 'amyloid' and 'Alzheimer's disease' for the years 1996–2009.

References

  1. Walker, L.C. & Cork, L.C. in Alzheimer Disease (eds. R.D. Terry et al.) 233–243 (Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA, 1999).

    Google Scholar 

  2. Gerlach, M. & Riederer, P. J. Neural Transm. 103, 987–1041 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Awano, T. et al. Proc. Natl. Acad. Sci. USA 106, 2794–2799 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cork, L.C. et al. J. Neuropathol. Exp. Neurol. 47, 629–641 (1988).

    Article  CAS  PubMed  Google Scholar 

  5. Price, D.L. et al. Brain Pathol. 1, 287–296 (1991).

    Article  CAS  Google Scholar 

  6. Cummings, B.J., Su, J.H., Cotman, C.W., White, R. & Russell, M. J. Neurobiol. Aging 14, 547–560 (1993).

    Article  CAS  Google Scholar 

  7. Walker, L.C. Brain Res. Brain Res. Rev. 25, 70–84 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Nelson, P.T., Greenberg, S.G. & Saper, C.B. Neurosci. Lett. 170, 187–190 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Schultz, C., Hubbard, G.B., Tredici, K.D., Braak, E. & Braak, H. Adv. Exp. Med. Biol. 487, 59–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Rosen, R.F. et al. J. Comp. Neurol. 509, 259–270 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Holzer, M., Craxton, M., Jakes, R., Arendt, T. & Goedert, M. Gene 341, 313–322 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Podlisny, M.B., Tolan, D.R. & Selkoe, D.J. Am. J. Pathol. 138, 1423–1435 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Fukuhara, R., Tezuka, T. & Kageyama, T. Gene 296, 99–109 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Hamilton, B.A. Genomics 83, 739–742 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Ryan, N.S. & Rossor, M.N. Biomark. Med. 4, 99–112 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Mackenzie, I.R.A. Lancet Neurol. (in the press).

  17. Turner, B.J. & Talbot, K. Prog. Neurobiol. 85, 94–134 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Gasser, T. Expert Rev. Mol. Med. 11, e22 (2009).

    Article  PubMed  Google Scholar 

  19. Götz, J. & Ittner, L.M. Nat. Rev. Neurosci. 9, 532–544 (2008).

    Article  PubMed  CAS  Google Scholar 

  20. Teschendorf, D. & Link, C.D. Mol. Neurodegener. 4, 38 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Duyckaerts, C., Potier, M.C. & Delatour, B. Acta Neuropathol. 115, 5–38 (2008).

    Article  PubMed  Google Scholar 

  22. Kahle, P.J. Acta Neuropathol. 115, 87–95 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Chesselet, M.F. Exp. Neurol. 209, 22–27 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Dawson, T.M., Ko, H.S. & Dawson, V.L. Neuron 66, 646–661 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zilka, N., Korenova, M. & Novak, M. Acta Neuropathol. 118, 71–86 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Denk, F. & Wade-Martins, R. Neurobiol. Aging 30, 1–13 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Chen-Plotkin, A.S., Lee, V.M. & Trojanowski, J.Q. Nat. Rev. Neurol. 6, 211–220 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hardy, J. & Selkoe, D.J. Science 297, 353–356 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Bertram, L. & Tanzi, R.E. Nat. Rev. Neurosci. 9, 768–778 (2008)

    Article  CAS  PubMed  Google Scholar 

  30. Herzig, M.C., Van Nostrand, W.E. & Jucker, M. Brain Pathol. 16, 40–54 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Klunk, W.E. et al. J. Neurosci. 25, 10598–10606 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kuo, Y.M. et al. J. Biol. Chem. 276, 12991–12998 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Maeda, J. et al. J. Neurosci. 27, 10957–10968 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rosen, R.F., Walker, L.C. & Levine, H. 3rd. Neurobiol. Aging published online, 10.1016/j.neurobiolaging.2009.02.011 (27 March 2009).

  35. Piccini, A. et al. J. Biol. Chem. 280, 34186–34192 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Levine, H. III & Walker, L.C. Neurobiol. Aging 31, 542–548 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Rosen, R.F. et al. Acta Neuropathol. 119, 221–233 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Gómez-Isla, T. et al. J. Neurosci. 16, 4491–4500 (1996).

    Article  PubMed  PubMed Central  Google Scholar 

  39. West, M.J., Coleman, P.D., Flood, D.G. & Troncoso, J.C. Lancet 344, 769–772 (1994).

    Article  CAS  PubMed  Google Scholar 

  40. Calhoun, M.E. et al. Nature 395, 755–756 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Rupp, N.J., Wegenast-Braun, B.M., Radde, R., Calhoun, M.E. & Jucker, M. Neurobiol. Aging (in the press).

  42. Morris, J.C. et al. Arch. Neurol. 66, 1469–1475 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ashe, K.H. Learn. Mem. 8, 301–308 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Chen, G. et al. Nature 408, 975–979 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Lesné, S. et al. Nature 440, 352–357 (2006).

    Article  PubMed  CAS  Google Scholar 

  46. Shankar, G.M. et al. Nat. Med. 14, 837–842 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dodart, J.C. et al. Nat. Neurosci. 5, 452–457 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Comery, T.A. et al. J. Neurosci. 25, 8898–8902 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Simón-Sánchez, J. et al. Nat. Genet. 41, 1308–1312 (2009).

    PubMed  PubMed Central  Google Scholar 

  50. Obeso, J.A. et al. Nat. Med. 16, 653–661 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Goedert, M. & Spillantini, M.G. Science 314, 777–781 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Heutink, P. Hum. Mol. Genet. 9, 979–986 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Sleegers, K., Cruts, M. & Van Broeckhoven, C. Annu. Rev. Neurosci. 33, 71–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Andorfer, C. et al. J. Neurochem. 86, 582–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Ishihara, T. et al. Am. J. Pathol. 158, 555–562 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Santacruz, K. et al. Science 309, 476–481 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. de Calignon, A. et al. Nature 464, 1201–1204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bento-Abreu, A., Van Damme, P., Van Den Bosch, L. & Robberecht, W. Eur. J. Neurosci. 31, 2247–2265 (2010).

    Article  PubMed  Google Scholar 

  59. Wils, H. et al. Proc. Natl. Acad. Sci. USA 107, 3858–3863 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wegorzewska, I., Bell, S., Cairns, N.J., Miller, T.M. & Baloh, R.H. Proc. Natl. Acad. Sci. USA 106, 18809–18814 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ahmed, Z. et al. Am. J. Pathol. 177, 311–324 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yin, F. et al. FASEB J. published online, 10.1096/fj.10-161471 (28 July 2010).

  63. Rosen, D.R. et al. Nature 362, 59–62 (1993).

    Article  CAS  PubMed  Google Scholar 

  64. Ilieva, H., Polymenidou, M. & Cleveland, D.W. J. Cell Biol. 187, 761–772 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Abbott, A. Nature 465, 410 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Beckers, J., Wurst, W. & de Angelis, M.H. Nat. Rev. Genet. 10, 371–380 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Traggiai, E. et al. Science 304, 104–107 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Hock, B.J. Jr. & Lamb, B.T. Trends Genet. 17, S7–S12 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Yazawa, I. et al. Neuron 45, 847–859 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Shults, C.W. et al. J. Neurosci. 25, 10689–10699 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Forman, M.S. et al. J. Neurosci. 25, 3539–3550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Higuchi, M. et al. J. Neurosci. 25, 9434–9443 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Meyer-Luehmann, M. et al. Science 313, 1781–1784 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Clavaguera, F. et al. Nat. Cell Biol. 11, 909–913 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Aguzzi, A. & Rajendran, L. Neuron 64, 783–790 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Oddo, S. et al. Neuron 39, 409–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Lewis, J. et al. Science 293, 1487–1491 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Bolmont, T. et al. Am. J. Pathol. 171, 2012–2020 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Terwel, D. et al. Am. J. Pathol. 172, 786–798 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Coomaraswamy, J. et al. Proc. Natl. Acad. Sci. USA 107, 7969–7974 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Games, D. et al. Nature 373, 523–527 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Schenk, D. et al. Nature 400, 173–177 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Bard, F. et al. Nat. Med. 6, 916–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Brody, D.L. & Holtzman, D.M. Annu. Rev. Neurosci. 31, 175–193 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nicoll, J.A. et al. Nat. Med. 9, 448–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Orgogozo, J.M. et al. Neurology 61, 46–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Furlan, R. et al. Brain 126, 285–291 (2003).

    Article  PubMed  Google Scholar 

  88. Lee, E.B., Leng, L.Z., Lee, V.M. & Trojanowski, J.Q. FEBS Lett. 579, 2564–2568 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Pfeifer, M. et al. Science 298, 1379 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Racke, M.M. et al. J. Neurosci. 25, 629–636 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Boche, D. et al. Brain 131, 3299–3310 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Rinne, J.O. et al. Lancet Neurol. 9, 363–372 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Holmes, C. et al. Lancet 372, 216–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Serrano-Pozo, A. et al. Brain 133, 1312–1327 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Salloway, S. et al. Neurology 73, 2061–2070 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zahs, K.R. & Ashe, K.H. Trends Neurosci. 33, 381–389 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. van der Worp, H.B. et al. PLoS Med. 7, e1000245 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Callahan, M.J. et al. Am. J. Pathol. 158, 1173–1177 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang, J., Tanila, H., Puolivali, J., Kadish, I. & van Groen, T. Neurobiol. Dis. 14, 318–327 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Benatar, M. Neurobiol. Dis. 26, 1–13 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Ludolph, A.C. et al. Amyotroph. Lateral Scler. 11, 38–45 (2010).

    Article  PubMed  Google Scholar 

  102. Harrison, D.E. et al. Nature 460, 392–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Blennow, K. Nat. Med. published online, 10.1038/nm.2221 (21 September 2010).

  104. Perrin, R.J., Fagan, A.M. & Holtzman, D.M. Nature 461, 916–922 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fuchs, H. et al. Curr. Pharm. Biotechnol. 10, 236–243 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Martin, B., Ji, S., Maudsley, S. & Mattson, M.P. Proc. Natl. Acad. Sci. USA 107, 6127–6133 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I would like to thank L. Walker and M. Staufenbiel for various discussions and help with this manuscript. The systematic review of the literature by R. Radde is greatly acknowledged. I also thank M. Neumann, V. Lee, J. McLaurin, D. Schenk, D. Thal, J. Götz, D. DiMonte, M. Goedert, T. Gasser and P. Kahle for comments on various parts of this commentary and the attendees of the Herrenhausen Symposium on Neurodegeneration for the inspiring discussions from which this commentary has emerged. The work was supported by the German National Genome Network (NGFNPlus).

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  1. Mathias Jucker is at the Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, and the DZNE-German Center for Neurodegenerative Diseases, Tübingen, Germany.,

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Jucker, M. The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med 16, 1210–1214 (2010). https://doi.org/10.1038/nm.2224

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