Cellular and Molecular Neurobiology

, Volume 29, Issue 6–7, pp 895–900

Cortical and Hippocampal Neurons from Truncated Tau Transgenic Rat Express Multiple Markers of Neurodegeneration

  • Peter Filipcik
  • Martin Cente
  • Gabriela Krajciova
  • Ivo Vanicky
  • Michal Novak
Original Paper

Abstract

Transition of protein tau from physiologically unfolded to misfolded state represent enigmatic step in the pathogenesis of tauopathies including Alzheimer’s disease (AD). Major molecular events playing role in this process involve truncation and hyperphosphorylation of tau protein, which are accompanied by redox imbalance followed by functional deterioration of neuronal network. Recently we have developed transgenic rat model showing that expression of truncated tau causes neurofibrillary degeneration similar to that observed in brain of AD sufferers. Consequently we tested cortical and hippocampal neuronal cultures extracted from this model as a convenient tool for development of molecules able to target the mechanisms leading to and/or enhancing the process of neurodegeneration. Here we document three major pathological features typical for tauopathies and AD in cortical and hippocampal neurons from transgenic rat in vitro. First, an increased accumulation of human truncated tau in neurons; second, the hyperphosphorylation of truncated tau on the epitopes characteristic of AD (Ser202/Thr205 and Thr231); and third, increased vulnerability of the neurons to nitrative and oxidative stress. Our results show that primary neurons expressing human truncated tau could represent a cellular model for targeting tau related pathological events, namely, aberrant tau protein accumulation, tau hyperphosphorylation, and oxidative/nitrative damage. These characteristics make the model particularly suitable for detailed study of molecular mechanisms of tau induced neurodegeneration and easily applicable for drug screening.

Keywords

Tau protein Primary neurons Sin-1 Cellular model 

References

  1. Aliev G, Smith MA, De la Torre JC, Perry G (2004) Mitochondria as a primary target for vascular hypoperfusion and oxidative stress in Alzheimer’s disease. Mitochondrion 4:649–663. doi:10.1016/j.mito.2004.07.018 PubMedCrossRefGoogle Scholar
  2. Alonso AC, Mederlyova A, Novak N, Grundke-Iqbal I, Iqbal K (2004) Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 279:34878–34881Google Scholar
  3. Bertram L, Tanzi RE (2005) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115:1449–1457. doi:10.1172/JCI24761 PubMedCrossRefGoogle Scholar
  4. Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259. doi:10.1007/BF00308809 PubMedCrossRefGoogle Scholar
  5. Butterfield DA, Perluigi M, Sultana R (2006) Oxidative stress in Alzheimer’s disease brain: new insights from redox proteomics. Eur J Pharmacol 545:39–50. doi:10.1016/j.ejphar.2006.06.026 PubMedCrossRefGoogle Scholar
  6. Cente M, Filipcik P, Pevalova M, Novak M (2006) Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J NeuroSci 24:1085–1090. doi:10.1111/j.1460-9568.2006.04986.x PubMedCrossRefGoogle Scholar
  7. Csokova N, Skrabana R, Liebig HD, Mederlyova A, Kontsek P, Novak M (2004) Rapid purification of truncated tau proteins: model approach to purification of functionally active fragments of disordered proteins, implication for neurodegenerative diseases. Protein Expr Purif 35:366–372. doi:10.1016/j.pep.2004.01.012 PubMedCrossRefGoogle Scholar
  8. Eide L, McMurray CT (2005) Culture of adult mouse neurons. Biotechniques 38:99–104. doi:10.2144/05381RR02 PubMedCrossRefGoogle Scholar
  9. Garcia-Sierra F, Ghoshal N, Quinn B, Berry RW, Binder LI (2003) Conformational changes and truncation of tau protein during tangle evolution in Alzheimer’s disease. J Alzheimers Dis 5:65–77PubMedGoogle Scholar
  10. Götz J, Deters N, Doldissen A, Bokhari L, Ke Y, Wiesner A, Schonrock N, Ittner LM (2007) A decade of tau transgenic animal models and beyond. Brain Pathol 17:91–103. doi:10.1111/j.1750-3639.2007.00051.x PubMedCrossRefGoogle Scholar
  11. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917. doi:10.1073/pnas.83.13.4913 PubMedCrossRefGoogle Scholar
  12. Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, Bennett DA, Cryns VL, Berry RW, Binder LI (2004) Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci 24:7895–7902. doi:10.1523/JNEUROSCI.1988-04.2004 PubMedCrossRefGoogle Scholar
  13. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739:198–210PubMedGoogle Scholar
  14. King ME (2005) Can tau filaments be both physiologically beneficial and toxic? Biochim Biophys Acta 1739:260–267PubMedGoogle Scholar
  15. Koson P, Zilka N, Kovac A, Kovacech B, Korenova M, Filipcik P, Novak M (2008) Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J Neurosci 28:239–246. doi:10.1111/j.1460-9568.2008.06329.x PubMedCrossRefGoogle Scholar
  16. Kril JJ, Patel S, Harding AJ, Halliday GM (2002) Neuron loss from the hippocampus of Alzheimer`s disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathol 103:370–376. doi:10.1007/s00401-001-0477-5 PubMedCrossRefGoogle Scholar
  17. Le Corre S, Klafki HW, Plesnila N, Hübinger G, Obermeier A, Sahagún H, Monse B, Seneci P, Lewis J, Eriksen J, Zehr C, Yue M, McGowan E, Dickson DW, Hutton M, Roder HM (2006) An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proc Natl Acad Sci USA 103:9673–9678. doi:10.1073/pnas.0602913103 PubMedCrossRefGoogle Scholar
  18. Moreira PI, Smith MA, Zhu X, Honda K, Lee HG, Aliev G, Perry G (2005) Oxidative damage and Alzheimer’s disease: are antioxidant therapies useful? Drug News Perspect 18:13–19. doi:10.1358/dnp.2005.18.1.877165 PubMedCrossRefGoogle Scholar
  19. Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58:188–197. doi:10.1097/00005072-199902000-00008 PubMedCrossRefGoogle Scholar
  20. Novak M (1994) Truncated tau protein as a new marker for Alzheimer’s disease. Acta Virol 38:173–189PubMedGoogle Scholar
  21. Novak M, Wischik CM, Edwards P, Pannell R, Milstein C (1989) Characterization of the first monoclonal antibody against the pronase resistant core of the Alzheimer PHF. Prog Clin Biol Res 317:755–761PubMedGoogle Scholar
  22. Novak M, Kabat J, Wischik CM (1993) Molecular characterization of the minimal protease resistant tau unit of the Alzheimer’s disease paired helical filament. EMBO J 12:365–370PubMedGoogle Scholar
  23. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421. doi:10.1016/S0896-6273(03)00434-3 PubMedCrossRefGoogle Scholar
  24. Perry G, Nunomura A, Hirai K, Zhu X, Perez M, Avila J, Castellani RJ, Atwood CS, Aliev G, Sayre LM, Takeda A, Smith MA (2002) Is oxidative damage the fundamental pathogenic mechanism of Alzheimer’s and other neurodegenerative diseases? Free Radic Biol Med 33:1475–1479. doi:10.1016/S0891-5849(02)01113-9 PubMedCrossRefGoogle Scholar
  25. Schindowski K, Bretteville A, Leroy K, Bégard S, Brion JP, Hamdane M, Buée L (2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169:599–616. doi:10.2353/ajpath.2006.060002 PubMedCrossRefGoogle Scholar
  26. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. doi:10.1126/science.1074069 PubMedCrossRefGoogle Scholar
  27. Watanabe A, Hong WK, Dohmae N, Takio K, Morishima-Kawashima M, Ihara Y (2004) Molecular aging of tau: disulfide-independent aggregation and non-enzymatic degradation in vitro and in vivo. J Neurochem 90:1302–1311. doi:10.1111/j.1471-4159.2004.02611.x PubMedCrossRefGoogle Scholar
  28. Wischik CM, Novak M, Thogersen HC, Edwards PC, Runswick MJ, Jakes R, Walker JE, Milstein C, Roth M, Klug A (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85:4506–4510. doi:10.1073/pnas.85.12.4506 PubMedCrossRefGoogle Scholar
  29. Zhang YJ, Xu YF, Liu YH, Yin J, Li HL, Wang Q, Wang JZ (2006) Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms. FASEB J 20:1431–1442. doi:10.1096/fj.05-5223com PubMedCrossRefGoogle Scholar
  30. Zilka N, Filipcik P, Koson P, Vechterova L, Skrabana R, Zilkova M, Rolkova G, Kontsekova E, Novak M (2006) Truncated tau from sporadic Alzheimer’s disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett 580:3582–3588. doi:10.1016/j.febslet.2006.05.029 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Peter Filipcik
    • 1
    • 2
  • Martin Cente
    • 1
  • Gabriela Krajciova
    • 1
  • Ivo Vanicky
    • 3
  • Michal Novak
    • 1
  1. 1.Institute of Neuroimmunology, Center of Excellence, SAVBratislavaSlovak Republic
  2. 2.Axon Neuroscience GmbHViennaAustria
  3. 3.Institute of Neurobiology, Center of Excellence, Slovak Academy of SciencesKosiceSlovak Republic

Personalised recommendations