Advertisement

Animal Models of Frontotemporal Dementia

  • Hana N. Dawson
  • Daniel T. Laskowitz
Protocol
Part of the Neuromethods book series (NM, volume 48)

Abstract

Frontotemporal dementia (FTD) is a multifaceted syndrome with a high degree of clinical and ­neuropathological variability, an extensive genetic contribution, and involvement of multiple proteins. FTD accounts for up to 50% of dementias with the onset prior to age 60. The heterogeneous genetic, clinical, and pathological manifestations of FTD have created challenges in generating clinically relevant animal models with which to test new therapeutic approaches. Nevertheless, tau transgenic models have been developed in mice, Drosophila melanogaster, and Caenorhabditis elegans in the past decade. These models have played an important role in elucidating a number of mechanisms associated with tau FTD-related neurodegeneration, and it is likely that these preclinical models will help to facilitate new therapeutic strategies. It is clear that both wild-type and mutated tau protein are sufficient to elicit tauopathy, although mutated tau increases the severity of the pathology. Furthermore, the aberrant expression and/or incorrect temporal/developmental expression of tau may also cause tau pathology. Importantly, these tau models have clarified some long-held theories pertaining to tau and neurodegeneration. For example, it has been shown that oxidative stress plays a crucial role in FTD and that tau pathology reactivates the cell cycle machinery. Conversely, tau aggregates are not necessary for tau neurotoxicity. However, new models representing other forms of FTD need to be developed and much work still remains before the disease is clearly understood and disease-modifying therapies become available.

Key words

FTD Animal models Transgenic Tau Progranulin TDP-43 Neurodegeneration 

References

  1. 1.
    Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8(9):663–672PubMedCrossRefGoogle Scholar
  2. 2.
    Pick A (1892) Über die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager medicinische Wochenschrift 17:165–167Google Scholar
  3. 3.
    Alzheimer A (1911) Uber eigenartige Krankheitsfalle des spateren Alters. Z Gesamte Neurol Psychia 4:356–385CrossRefGoogle Scholar
  4. 4.
    Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG (2005) The evolution and pathology of frontotemporal dementia. Brain 128(Pt 9):1996–2005PubMedCrossRefGoogle Scholar
  5. 5.
    Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51(6):1546–1554PubMedGoogle Scholar
  6. 6.
    Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002) The prevalence of frontotemporal dementia. Neurology 58(11):1615–1621PubMedGoogle Scholar
  7. 7.
    Rosso SM, Donker KL, Baks T et al (2003) Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 126(Pt 9):2016–2022PubMedCrossRefGoogle Scholar
  8. 8.
    Brun A (1987) Frontal lobe degeneration of non-Alzheimer type. I. Neuropathology. Arch Gerontol Geriatr 6(3):193–208PubMedCrossRefGoogle Scholar
  9. 9.
    Hutton M, Lendon CL, Rizzu P et al (1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393(6686):702–705PubMedCrossRefGoogle Scholar
  10. 10.
    Poorkaj P, Bird TD, Wijsman E et al (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43(6):815–825PubMedCrossRefGoogle Scholar
  11. 11.
    Baker M, Mackenzie IR, Pickering-Brown SM et al (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442(7105):916–919PubMedCrossRefGoogle Scholar
  12. 12.
    Cruts M, Gijselinck I, van der ZJ et al (2006) Null mutations in progranulin cause ­ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442(7105): 920–924PubMedCrossRefGoogle Scholar
  13. 13.
    Watts GD, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36(4):377–381PubMedCrossRefGoogle Scholar
  14. 14.
    Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D’Amato CJ, Gilman S (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 41(6):706–715PubMedCrossRefGoogle Scholar
  15. 15.
    Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 95(13):7737–7741PubMedCrossRefGoogle Scholar
  16. 16.
    Alzheimer Disease & Frontotemporal Dementia Mutation Database (2009). 2-23-2009. Ref Type: Internet CommunicationGoogle Scholar
  17. 17.
    Mukherjee O, Pastor P, Cairns NJ et al (2006) HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 60(3):314–322PubMedCrossRefGoogle Scholar
  18. 18.
    Gijselinck I, Van BC, Cruts M (2008) Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum Mutat 29(12):1373–1386PubMedCrossRefGoogle Scholar
  19. 19.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133PubMedCrossRefGoogle Scholar
  20. 20.
    Winton MJ, Igaz LM, Wong MM, Kwong LK, Trojanowski JQ, Lee VM (2008) Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease­-like redistribution, sequestration, and aggregate formation. J Biol Chem 283(19):13302–13309PubMedCrossRefGoogle Scholar
  21. 21.
    Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351(3):602–611PubMedCrossRefGoogle Scholar
  22. 22.
    Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63(4):535–538PubMedCrossRefGoogle Scholar
  23. 23.
    Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40(5):572–574PubMedCrossRefGoogle Scholar
  24. 24.
    Yokoseki A, Shiga A, Tan CF et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63(4):538–542PubMedCrossRefGoogle Scholar
  25. 25.
    Forman MS, Mackenzie IR, Cairns NJ et al (2006) Novel ubiquitin neuropathology in frontotemporal dementia with valosin-­containing protein gene mutations. J Neuropathol Exp Neurol 65(6):571–581PubMedCrossRefGoogle Scholar
  26. 26.
    Neumann M, Mackenzie IR, Cairns NJ et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66(2): 152–157PubMedCrossRefGoogle Scholar
  27. 27.
    Kimonis VE, Kovach MJ, Waggoner B et al (2000) Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet Med 2(4):232–241PubMedCrossRefGoogle Scholar
  28. 28.
    Kovach MJ, Waggoner B, Leal SM et al (2001) Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Mol Genet Metab 74(4):458–475PubMedCrossRefGoogle Scholar
  29. 29.
    Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101(4):1371–1378PubMedCrossRefGoogle Scholar
  30. 30.
    Caceres A, Kosik KS (1990) Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 343(6257):461–463PubMedCrossRefGoogle Scholar
  31. 31.
    Drubin DG, Caput D, Kirschner MW (1984) Studies on the expression of the microtubule-associated protein, tau, during mouse brain development, with newly isolated complementary DNA probes. J Cell Biol 98(3):1090–1097PubMedCrossRefGoogle Scholar
  32. 32.
    Ebneth A, Godemann R, Stamer K, Illenberger S, Trinczek B, Mandelkow E (1998) Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer’s disease. J Cell Biol 143(3):777–794PubMedCrossRefGoogle Scholar
  33. 33.
    Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156(6):1051–1063PubMedCrossRefGoogle Scholar
  34. 34.
    Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 72(5):1858–1862PubMedCrossRefGoogle Scholar
  35. 35.
    Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8(2):393–399PubMedGoogle Scholar
  36. 36.
    Himmler A, Drechsel D, Kirschner MW, Martin DW Jr (1989) Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol 9(4):1381–1388PubMedGoogle Scholar
  37. 37.
    Himmler A (1989) Structure of the bovine tau gene: alternatively spliced transcripts generate a protein family. Mol Cell Biol 9(4): 1389–1396PubMedGoogle Scholar
  38. 38.
    Goedert M, Jakes R (1990) Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J 9(13):4225–4230PubMedGoogle Scholar
  39. 39.
    Shahani N, Brandt R (2002) Functions and malfunctions of the tau proteins. Cell Mol Life Sci 59(10):1668–1680PubMedCrossRefGoogle Scholar
  40. 40.
    Gotz J, Probst A, Spillantini MG et al (1995) Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 14(7):1304–1313.PubMedGoogle Scholar
  41. 41.
    Spittaels K, Van den HC, Van DJ et al (1999) Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing ­four-repeat human tau protein. Am J Pathol 155(6): 2153–2165PubMedCrossRefGoogle Scholar
  42. 42.
    Probst A, Gotz J, Wiederhold KH et al (2000) Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol (Berl) 99(5):469–481CrossRefGoogle Scholar
  43. 43.
    Brion JP, Tremp G, Octave JN (1999) Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer’s disease. Am J Pathol 154(1):255–270PubMedCrossRefGoogle Scholar
  44. 44.
    Ishihara T, Hong M, Zhang B et al (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24(3):751–762PubMedCrossRefGoogle Scholar
  45. 45.
    Duff K, Knight H, Refolo LM et al (2000) Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis 7(2):87–98PubMedCrossRefGoogle Scholar
  46. 46.
    Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 114(Pt 6):1179–1187PubMedGoogle Scholar
  47. 47.
    Dawson HN, Cantillana V, Chen L, Vitek MP (2007) The tau N279K exon 10 splicing mutation recapitulates frontotemporal dementia and parkinsonism linked to chromosome 17 tauopathy in a mouse model. J Neurosci 27(34):9155–9168PubMedCrossRefGoogle Scholar
  48. 48.
    Yoshiyama Y, Lee VM, Trojanowski JQ (2001) Frontotemporal dementia and tauopathy. Curr Neurol Neurosci Rep 1(5):413–421PubMedCrossRefGoogle Scholar
  49. 49.
    Lewis J, McGowan E, Rockwood J et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25(4):402–405PubMedGoogle Scholar
  50. 50.
    Gotz J, Chen F, Barmettler R, Nitsch RM (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276(1):529–534PubMedGoogle Scholar
  51. 51.
    Gotz J, Tolnay M, Barmettler R, Chen F, Probst A, Nitsch RM (2001) Oligodendroglial tau filament formation in transgenic mice expressing G272V tau. Eur J Neurosci 13(11):2131–2140PubMedCrossRefGoogle Scholar
  52. 52.
    Allen B, Ingram E, Takao M et al (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22(21):9340–9351PubMedGoogle Scholar
  53. 53.
    Tanemura K, Murayama M, Akagi T et al (2002) Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci 22(1):133–141PubMedGoogle Scholar
  54. 54.
    Tatebayashi Y, Miyasaka T, Chui DH et al (2002) Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau. Proc Natl Acad Sci U S A 99(21):13896–13901PubMedCrossRefGoogle Scholar
  55. 55.
    SantaCruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309(5733):476–481PubMedCrossRefGoogle Scholar
  56. 56.
    Rademakers R, Cruts M, Van BC (2004) The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24(4):277–295PubMedCrossRefGoogle Scholar
  57. 57.
    Reed LA, Wszolek ZK, Hutton M (2001) Phenotypic correlations in FTDP-17. Neurobiol Aging 22(1):89–107PubMedCrossRefGoogle Scholar
  58. 58.
    Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130PubMedCrossRefGoogle Scholar
  59. 59.
    Forman MS, Trojanowski JQ, Lee VM (2004) Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs. Nat Med 10(10):1055–1063PubMedCrossRefGoogle Scholar
  60. 60.
    Goedert M, Hasegawa M (1999) The tauopathies: toward an experimental animal model. Am J Pathol 154(1):1–6PubMedCrossRefGoogle Scholar
  61. 61.
    Katsuse O, Iseki E, Arai T et al (2003) 4-repeat tauopathy sharing pathological and biochemical features of corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol (Berl) 106(3):251–260CrossRefGoogle Scholar
  62. 62.
    Morris HR, Osaki Y, Holton J et al (2003) Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP. Neurology 61(1):102–104PubMedGoogle Scholar
  63. 63.
    Sergeant N, Wattez A, Delacourte A (1999) Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J Neurochem 72(3):1243–1249PubMedCrossRefGoogle Scholar
  64. 64.
    Togo T, Sahara N, Yen SH et al (2002) Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 61(6):547–556PubMedGoogle Scholar
  65. 65.
    Wittmann CW, Wszolek MF, Shulman JM et al (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293(5530):711–714PubMedCrossRefGoogle Scholar
  66. 66.
    Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD (2003) Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci USA 100(17):9980–9985PubMedCrossRefGoogle Scholar
  67. 67.
    Miyasaka T, Ding Z, Gengyo-Ando K et al (2005) Progressive neurodegeneration in C. elegans model of tauopathy. Neurobiol Dis 20(2):372–383PubMedCrossRefGoogle Scholar
  68. 68.
    Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB (2007) Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 117(1):236–245PubMedCrossRefGoogle Scholar
  69. 69.
    Illenberger S, Zheng-Fischhofer Q, Preuss U et al (1998) The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer’s disease. Mol Biol Cell 9(6):1495–1512PubMedGoogle Scholar
  70. 70.
    Steinhilb ML, as-Santagata D, Fulga TA, Felch DL, Feany MB (2007) Tau phosphorylation sites work in concert to promote ­neurotoxicity in vivo. Mol Biol Cell 18(12): 5060–5068PubMedCrossRefGoogle Scholar
  71. 71.
    Kayasuga Y, Chiba S, Suzuki M et al (2007) Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 185(2):110–118PubMedCrossRefGoogle Scholar
  72. 72.
    Haass C (2009) Proteolytic Processing and Aggregatopm of TAR DNA Binding Protein-43 After Caspase Activation. Alzheimer’s & Parkinson’s Diseases: 9th International Conference 2009, Prague Czech Republic, 2009Google Scholar
  73. 73.
    Ayala YM, Pantano S, D’Ambrogio A et al (2005) Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. J Mol Biol 348(3):575–588PubMedCrossRefGoogle Scholar
  74. 74.
    Winton MJ, Van DV, Kwong LK et al (2008) A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett 582(15):2252–2256PubMedCrossRefGoogle Scholar
  75. 75.
    Ayala YM, Misteli T, Baralle FE (2008) TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression. Proc Natl Acad Sci USA 105(10):3785–3789PubMedCrossRefGoogle Scholar
  76. 76.
    Modeling Aspects of Frontotemporal Dementia in Zebrafish. Alzheimer’s & Parkinson’s Diseases: 9th International Conference 2009, Prague, Czech Republic; 2009.Google Scholar
  77. 77.
    Lu KP, Zhou XZ (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 8(11):904–916PubMedCrossRefGoogle Scholar
  78. 78.
    Lim J, Balastik M, Lee TH et al (2008) Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. J Clin Invest 118(5):1877–1889PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Hana N. Dawson
    • 1
  • Daniel T. Laskowitz
    • 1
  1. 1.Division of NeurologyDuke UniversityDurhamUSA

Personalised recommendations