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.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Structured tracking of alcohol reinforcement (STAR) for basic and translational alcohol research
Molecular Psychiatry Open Access 27 February 2023
-
Reduced and stable feature sets selection with random forest for neurons segmentation in histological images of macaque brain
Scientific Reports Open Access 26 November 2021
-
Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy
Scientific Reports Open Access 06 August 2021
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
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).
Gerlach, M. & Riederer, P. J. Neural Transm. 103, 987–1041 (1996).
Awano, T. et al. Proc. Natl. Acad. Sci. USA 106, 2794–2799 (2009).
Cork, L.C. et al. J. Neuropathol. Exp. Neurol. 47, 629–641 (1988).
Price, D.L. et al. Brain Pathol. 1, 287–296 (1991).
Cummings, B.J., Su, J.H., Cotman, C.W., White, R. & Russell, M. J. Neurobiol. Aging 14, 547–560 (1993).
Walker, L.C. Brain Res. Brain Res. Rev. 25, 70–84 (1997).
Nelson, P.T., Greenberg, S.G. & Saper, C.B. Neurosci. Lett. 170, 187–190 (1994).
Schultz, C., Hubbard, G.B., Tredici, K.D., Braak, E. & Braak, H. Adv. Exp. Med. Biol. 487, 59–69 (2001).
Rosen, R.F. et al. J. Comp. Neurol. 509, 259–270 (2008).
Holzer, M., Craxton, M., Jakes, R., Arendt, T. & Goedert, M. Gene 341, 313–322 (2004).
Podlisny, M.B., Tolan, D.R. & Selkoe, D.J. Am. J. Pathol. 138, 1423–1435 (1991).
Fukuhara, R., Tezuka, T. & Kageyama, T. Gene 296, 99–109 (2002).
Hamilton, B.A. Genomics 83, 739–742 (2004).
Ryan, N.S. & Rossor, M.N. Biomark. Med. 4, 99–112 (2010).
Mackenzie, I.R.A. Lancet Neurol. (in the press).
Turner, B.J. & Talbot, K. Prog. Neurobiol. 85, 94–134 (2008).
Gasser, T. Expert Rev. Mol. Med. 11, e22 (2009).
Götz, J. & Ittner, L.M. Nat. Rev. Neurosci. 9, 532–544 (2008).
Teschendorf, D. & Link, C.D. Mol. Neurodegener. 4, 38 (2009).
Duyckaerts, C., Potier, M.C. & Delatour, B. Acta Neuropathol. 115, 5–38 (2008).
Kahle, P.J. Acta Neuropathol. 115, 87–95 (2008).
Chesselet, M.F. Exp. Neurol. 209, 22–27 (2008).
Dawson, T.M., Ko, H.S. & Dawson, V.L. Neuron 66, 646–661 (2010).
Zilka, N., Korenova, M. & Novak, M. Acta Neuropathol. 118, 71–86 (2009).
Denk, F. & Wade-Martins, R. Neurobiol. Aging 30, 1–13 (2009).
Chen-Plotkin, A.S., Lee, V.M. & Trojanowski, J.Q. Nat. Rev. Neurol. 6, 211–220 (2010).
Hardy, J. & Selkoe, D.J. Science 297, 353–356 (2002).
Bertram, L. & Tanzi, R.E. Nat. Rev. Neurosci. 9, 768–778 (2008)
Herzig, M.C., Van Nostrand, W.E. & Jucker, M. Brain Pathol. 16, 40–54 (2006).
Klunk, W.E. et al. J. Neurosci. 25, 10598–10606 (2005).
Kuo, Y.M. et al. J. Biol. Chem. 276, 12991–12998 (2001).
Maeda, J. et al. J. Neurosci. 27, 10957–10968 (2007).
Rosen, R.F., Walker, L.C. & Levine, H. 3rd. Neurobiol. Aging published online, 10.1016/j.neurobiolaging.2009.02.011 (27 March 2009).
Piccini, A. et al. J. Biol. Chem. 280, 34186–34192 (2005).
Levine, H. III & Walker, L.C. Neurobiol. Aging 31, 542–548 (2010).
Rosen, R.F. et al. Acta Neuropathol. 119, 221–233 (2010).
Gómez-Isla, T. et al. J. Neurosci. 16, 4491–4500 (1996).
West, M.J., Coleman, P.D., Flood, D.G. & Troncoso, J.C. Lancet 344, 769–772 (1994).
Calhoun, M.E. et al. Nature 395, 755–756 (1998).
Rupp, N.J., Wegenast-Braun, B.M., Radde, R., Calhoun, M.E. & Jucker, M. Neurobiol. Aging (in the press).
Morris, J.C. et al. Arch. Neurol. 66, 1469–1475 (2009).
Ashe, K.H. Learn. Mem. 8, 301–308 (2001).
Chen, G. et al. Nature 408, 975–979 (2000).
Lesné, S. et al. Nature 440, 352–357 (2006).
Shankar, G.M. et al. Nat. Med. 14, 837–842 (2008).
Dodart, J.C. et al. Nat. Neurosci. 5, 452–457 (2002).
Comery, T.A. et al. J. Neurosci. 25, 8898–8902 (2005).
Simón-Sánchez, J. et al. Nat. Genet. 41, 1308–1312 (2009).
Obeso, J.A. et al. Nat. Med. 16, 653–661 (2010).
Goedert, M. & Spillantini, M.G. Science 314, 777–781 (2006).
Heutink, P. Hum. Mol. Genet. 9, 979–986 (2000).
Sleegers, K., Cruts, M. & Van Broeckhoven, C. Annu. Rev. Neurosci. 33, 71–88 (2010).
Andorfer, C. et al. J. Neurochem. 86, 582–590 (2003).
Ishihara, T. et al. Am. J. Pathol. 158, 555–562 (2001).
Santacruz, K. et al. Science 309, 476–481 (2005).
de Calignon, A. et al. Nature 464, 1201–1204 (2010).
Bento-Abreu, A., Van Damme, P., Van Den Bosch, L. & Robberecht, W. Eur. J. Neurosci. 31, 2247–2265 (2010).
Wils, H. et al. Proc. Natl. Acad. Sci. USA 107, 3858–3863 (2010).
Wegorzewska, I., Bell, S., Cairns, N.J., Miller, T.M. & Baloh, R.H. Proc. Natl. Acad. Sci. USA 106, 18809–18814 (2009).
Ahmed, Z. et al. Am. J. Pathol. 177, 311–324 (2010).
Yin, F. et al. FASEB J. published online, 10.1096/fj.10-161471 (28 July 2010).
Rosen, D.R. et al. Nature 362, 59–62 (1993).
Ilieva, H., Polymenidou, M. & Cleveland, D.W. J. Cell Biol. 187, 761–772 (2009).
Abbott, A. Nature 465, 410 (2010).
Beckers, J., Wurst, W. & de Angelis, M.H. Nat. Rev. Genet. 10, 371–380 (2009).
Traggiai, E. et al. Science 304, 104–107 (2004).
Hock, B.J. Jr. & Lamb, B.T. Trends Genet. 17, S7–S12 (2001).
Yazawa, I. et al. Neuron 45, 847–859 (2005).
Shults, C.W. et al. J. Neurosci. 25, 10689–10699 (2005).
Forman, M.S. et al. J. Neurosci. 25, 3539–3550 (2005).
Higuchi, M. et al. J. Neurosci. 25, 9434–9443 (2005).
Meyer-Luehmann, M. et al. Science 313, 1781–1784 (2006).
Clavaguera, F. et al. Nat. Cell Biol. 11, 909–913 (2009).
Aguzzi, A. & Rajendran, L. Neuron 64, 783–790 (2009).
Oddo, S. et al. Neuron 39, 409–421 (2003).
Lewis, J. et al. Science 293, 1487–1491 (2001).
Bolmont, T. et al. Am. J. Pathol. 171, 2012–2020 (2007).
Terwel, D. et al. Am. J. Pathol. 172, 786–798 (2008).
Coomaraswamy, J. et al. Proc. Natl. Acad. Sci. USA 107, 7969–7974 (2010).
Games, D. et al. Nature 373, 523–527 (1995).
Schenk, D. et al. Nature 400, 173–177 (1999).
Bard, F. et al. Nat. Med. 6, 916–919 (2000).
Brody, D.L. & Holtzman, D.M. Annu. Rev. Neurosci. 31, 175–193 (2008).
Nicoll, J.A. et al. Nat. Med. 9, 448–452 (2003).
Orgogozo, J.M. et al. Neurology 61, 46–54 (2003).
Furlan, R. et al. Brain 126, 285–291 (2003).
Lee, E.B., Leng, L.Z., Lee, V.M. & Trojanowski, J.Q. FEBS Lett. 579, 2564–2568 (2005).
Pfeifer, M. et al. Science 298, 1379 (2002).
Racke, M.M. et al. J. Neurosci. 25, 629–636 (2005).
Boche, D. et al. Brain 131, 3299–3310 (2008).
Rinne, J.O. et al. Lancet Neurol. 9, 363–372 (2010).
Holmes, C. et al. Lancet 372, 216–223 (2008).
Serrano-Pozo, A. et al. Brain 133, 1312–1327 (2010).
Salloway, S. et al. Neurology 73, 2061–2070 (2009).
Zahs, K.R. & Ashe, K.H. Trends Neurosci. 33, 381–389 (2010).
van der Worp, H.B. et al. PLoS Med. 7, e1000245 (2010).
Callahan, M.J. et al. Am. J. Pathol. 158, 1173–1177 (2001).
Wang, J., Tanila, H., Puolivali, J., Kadish, I. & van Groen, T. Neurobiol. Dis. 14, 318–327 (2003).
Benatar, M. Neurobiol. Dis. 26, 1–13 (2007).
Ludolph, A.C. et al. Amyotroph. Lateral Scler. 11, 38–45 (2010).
Harrison, D.E. et al. Nature 460, 392–395 (2009).
Blennow, K. Nat. Med. published online, 10.1038/nm.2221 (21 September 2010).
Perrin, R.J., Fagan, A.M. & Holtzman, D.M. Nature 461, 916–922 (2009).
Fuchs, H. et al. Curr. Pharm. Biotechnol. 10, 236–243 (2009).
Martin, B., Ji, S., Maudsley, S. & Mattson, M.P. Proc. Natl. Acad. Sci. USA 107, 6127–6133 (2010).
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).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2224
This article is cited by
-
Structured tracking of alcohol reinforcement (STAR) for basic and translational alcohol research
Molecular Psychiatry (2023)
-
Beyond animal models: revolutionizing neurodegenerative disease modeling using 3D in vitro organoids, microfluidic chips, and bioprinting
Cell and Tissue Research (2023)
-
Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy
Scientific Reports (2021)
-
Reduced and stable feature sets selection with random forest for neurons segmentation in histological images of macaque brain
Scientific Reports (2021)
-
Changes in RNA expression levels during antidepressant treatment: a systematic review
Journal of Neural Transmission (2021)