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Tau Transgenic Mouse Models in Therapeutic Development

  • Hanno M. Roder
Chapter

Abstract

Although a unifying animal model of Alzheimer’s disease (AD) has not been forthcoming, specific pathological features have been successfully induced in transgenic mice with mutated human genes identified by genetic analysis. A particular problem is that the defining pathologies of AD, amyloid-β peptide amyloidosis, and neurofibrillary tangles formed by the abnormally modified microtubule-associated protein tau cannot both be induced by a single mutation as in humans, calling in question straightforward cause–effect hypotheses. On the contrary, the separate manifestation of these pathologies in mice points to their distinct functional consequences: amyloid-β pathology interferes with synaptic efficiency but does not by itself drive neurodegeneration, while tau pathology appears to be the direct mechanism of neuronal degeneration and brain atrophy. In both cases, however, the latest data favor a dominant role of biochemical precursors to the obvious neuropathological structures, which originally defined the disease. In any case, for therapeutic development, tau pathology needs to be addressed for lasting treatment results in AD. Initial therapeutic studies with mouse models of tauopathy support their utility in the discovery of antineurodegenerative therapeutic principles. Moreover, certain aspects of tau pathology and their functional consequences may be partially reversible. Apart from such immediate utility, transgenic mouse models also promise to provide unique insights into the biochemical details of tau pathology, which are impossible to obtain from human AD brains.

Keywords

Paired Helical Filament Abnormal Hyperphosphorylation JNPL3 Mouse Broad Kinase Inhibitory Spectrum Conditional Transgenic Mouse Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Dickson DW, Crystal HA, Mattiace LA (1992) Identification of normal and pathological aging in prospectively studied non-demented elderly humans. Neurobiol Aging 13:179–189PubMedCrossRefGoogle Scholar
  2. 2.
    Armstrong RA (1994) Beta-amyloid (Abeta) deposition in elderly non-demented patients and patients with Alzheimer’s disease. Neurosci Lett 178:59–62PubMedCrossRefGoogle Scholar
  3. 3.
    Davis DG, Schmitt FA, Wekstein DR, Markesberry WR (1999) Alzheimer neuropathologic alterations in aged cognitively normal subjects. J Neuropathol Exp Neurol 58:376–388PubMedCrossRefGoogle Scholar
  4. 4.
    Knopman DS, Parisi JE, Salviati A (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62:1087–1095PubMedGoogle Scholar
  5. 5.
    Josephs KA, Whitwell JL, Ahmed Z et al (2008) Beta-amyloid burden is not associated with rates of brain atrophy. Ann Neurol 63:204–212.Google Scholar
  6. 6.
    Piccini A, Russo C, Gliozzi A (2005) β-Amyloid is different in normal aging and in Alzheimer’s disease. J Biol Chem 280:34186–34192PubMedCrossRefGoogle Scholar
  7. 7.
    Markesbery WR, Schmitt FA, Kryscio RJ (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46PubMedCrossRefGoogle Scholar
  8. 8.
    Goate A, Chartier-Harlin MC, Mullan M (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–706PubMedCrossRefGoogle Scholar
  9. 9.
    Lannfelt L, Bogdanovic N, Appelgren H (1994) Amyloid precursor protein mutation causes Alzheimer’s disease in a Swedish family. Neurosci Lett 168:254–256PubMedCrossRefGoogle Scholar
  10. 10.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356PubMedCrossRefGoogle Scholar
  11. 11.
    Haass C, Lemere CA, Capell A (1995) The Swedish mutation causes early-onset Alzheimer’s disease by beta-secretase cleavage within the secretory pathway. Nat Med 1:1291–1296PubMedCrossRefGoogle Scholar
  12. 12.
    Mehta ND, Refolo LM, Eckman C (1998) Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol 43:256–258PubMedCrossRefGoogle Scholar
  13. 13.
    Walker ES, Martinez M, Brunkan AL, Goate A (2005) Presenilin 2 familial Alzheimer’s disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem 92:294–301PubMedCrossRefGoogle Scholar
  14. 14.
    Irizarry MC, Soriano F, McNamara M (1997) Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci 17:7053–7059PubMedGoogle Scholar
  15. 15.
    Takeuchi A, Irizarry MC, Duff K (2000) Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss. Am J Pathol 157:331–339PubMedCrossRefGoogle Scholar
  16. 16.
    Lesne S, Koh MT, Kotilinek L (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357PubMedCrossRefGoogle Scholar
  17. 17.
    Lesne S, Kotilinek L, Ashe KH (2008) Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 151:745–749PubMedCrossRefGoogle Scholar
  18. 18.
    Dodart JC, Bales KR, Gannon KS (2002) Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer’s disease model. Nat Neurosci 5:452–457PubMedGoogle Scholar
  19. 19.
    Kotilinek LA, Bacskai B, Westerman M (2002) Reversible memory loss in a mouse transgenic model of Alzheimer’s disease. J Neurosci 22:6331–6335PubMedGoogle Scholar
  20. 20.
    Gilman S, Koller M, Black RS (2005) Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–1562PubMedCrossRefGoogle Scholar
  21. 21.
    Nicoll JA, Wilkinson D, Holmes C (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448–452PubMedCrossRefGoogle Scholar
  22. 22.
    Xu G, Gonzales V, Borchelt DR (2002) Abeta deposition does not cause the aggregation of endogenous tau in transgenic mice. Alzheimer Dis Assoc Disord 16:196–201PubMedCrossRefGoogle Scholar
  23. 23.
    Boutajangout A, Authelet M, Blanchard V (2004) Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer’s disease mutants of APP and presenilin-1. Neurobiol Dis 15:47–60PubMedCrossRefGoogle Scholar
  24. 24.
    Lewis J, Dickson DW, Lin WL (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491PubMedCrossRefGoogle Scholar
  25. 25.
    Goetz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495CrossRefGoogle Scholar
  26. 26.
    Bolmont T, Clavaguera F, Meyer-Luehmann M (2007) Induction of tau pathology by intracerebral infusion of amyloid-beta containing brain extract and by amyloid deposition in APP x tau transgenic mice. Am J Pathol 171:2012–2020PubMedCrossRefGoogle Scholar
  27. 27.
    Kulic L, Kurosinski P, Chen F (2006) Active immunization trial in Abeta42-injected P301L tau transgenic mice. Neurobiol Dis 22:50–56PubMedCrossRefGoogle Scholar
  28. 28.
    Jicha GA, Parisi JE, Dickson DW (2006) Neuropathologic outcome of mild cognitive impairment following progression to clinical dementia. Arch Neurol 63:674–681PubMedCrossRefGoogle Scholar
  29. 29.
    Hutton M, Lendon CL, Rizzu P (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705PubMedCrossRefGoogle Scholar
  30. 30.
    Lewis J, McGowan E, Rockwood J (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405PubMedCrossRefGoogle Scholar
  31. 31.
    Ramsden M, Kotilinek L, Forster C (2005) Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci 25:10637–10647PubMedCrossRefGoogle Scholar
  32. 32.
    Sahara N, Lewis J, DeTure M (2002) Assembly of tau in transgenic animals expressing P301L tau: alteration of phosphorylation and solubility. J Neurochem 83:1498–1508PubMedCrossRefGoogle Scholar
  33. 33.
    Mailliot C, Sergeant N, Bussiere T (1998) Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes. FEBS Lett 433:201–204PubMedCrossRefGoogle Scholar
  34. 34.
    Luo W, Dou F, Rodina A (2007) Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc Natl Acad Sci USA 104:9511–9516PubMedCrossRefGoogle Scholar
  35. 35.
    Noble W, Planel E, Zehr C (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990–6995PubMedCrossRefGoogle Scholar
  36. 36.
    Sakar S, Floto RA, Berger Z (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170:1101–1111CrossRefGoogle Scholar
  37. 37.
    LeCorre S, Klafki HW, Plesnila N (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc Natl Acad Sci USA 103:9673–9678CrossRefGoogle Scholar
  38. 38.
    Huebinger G, Geis S, LeCorre S (2008) Inhibition of PHF-like tau hyperphosphorylation in SH-SY5Y cells and rat brain slices by K252a. J Alzheimers Dis 13(3):281–294Google Scholar
  39. 39.
    Berger Z, Roder H, Hanna A (2007) Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650–3662PubMedCrossRefGoogle Scholar
  40. 40.
    Spires TL, Orne JD, Santacruz K (2006) Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 168:1598–1607PubMedCrossRefGoogle Scholar
  41. 41.
    Andorfer C, Kress Y, Espinoza M (2003) Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 86:582–560PubMedCrossRefGoogle Scholar
  42. 42.
    Santacruz K, Lewis J, Spires T (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Hanno M. Roder
    • 1
  1. 1.Tau Ta Tis, Inc.Jacksonville

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