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Stages of Pathological Tau-Protein Processing in Alzheimer’s Disease: From Soluble Aggregations to Polymerization into Insoluble Tau-PHFs

  • Raúl Mena
  • José Luna-Muñoz
Chapter

Abstract

Hyperphosphorylation and truncation have been proposed as key events in the abnormal tau-protein processing leading to the genesis of paired helical filaments. A recent hypothesis involving conformational changes has been emerging. However, the majority of studies have been based on the analysis of overt tangles. All the existing antibodies have been raised against normal, pathological tau protein, or intracellular tangles. It is possible that only those events occurring massively may be detected when observations are restricted to this type of structure, therefore, missing less-evident events. In general, it has been difficult to determine the early stages of tau processing in Alzheimer’s disease. By the use of selected tau markers and confocal microscopy in double and triple immunolabeling and the combination with thiazin red, we have been able to determine a morphological model and the underlying molecular mechanism involved in early stages of tau-protein abnormal processing. This molecular mechanism is characterized by a hierarchical sequence of events of phosphorylation and truncation resulting in conformational misfolding along the tau molecule. We have included some speculations regarding the possible triggers of such a cascade of pathological changes of tau based on the hypothesis of truncated tau as a highly stable tau fragment with a special high affinity to bind tau monomers. Relationships between phosphorylation and the truncated mechanism are also discussed.

Keywords

Paired Helical Filament Triple Immunolabeling AT100 Epitope Intracellular Tangle Modeling Early Stage 
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.

Notes

Acknowledgments

Authors express their gratitude to Dr. P. Davies (Albert Einstein College of Medicine, Bronx, NY, USA) for the generous gift of mAbs TG-3, Alz-50, and MC1, Mr. José L. Fernández for handling of the brain tissue, and Ms. Maricarmen De Lorenz for her secretarial assistance. This work was financially supported by CONACyT grants, No. 47630 (to R.M.). Thanks to Dr. Ellis Glazier for editing the English-language text.

References

  1. 1.
    Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT (1992) Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology 42: 631–639PubMedGoogle Scholar
  2. 2.
    Kidd M (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197: 192–193PubMedCrossRefGoogle Scholar
  3. 3.
    Kondo J, Honda T, Mori H, (1988) The carboxyl third of tau is tightly bound to paired helical filaments. Neuron 1: 827–834PubMedCrossRefGoogle Scholar
  4. 4.
    Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87: 554–567PubMedCrossRefGoogle Scholar
  5. 5.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259PubMedCrossRefGoogle Scholar
  6. 6.
    Mena R, Edwards PC, Harrington CR, (1996) Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer’s disease. Acta Neuropathol 91: 633–641PubMedCrossRefGoogle Scholar
  7. 7.
    Goedert M, Jakes R, Crowther RA, (1993) The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci USA 90: 5066–5070PubMedCrossRefGoogle Scholar
  8. 8.
    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
  9. 9.
    Trojanowski JQ, Schmidt ML, Shin RW, (1993) Altered tau and neurofilament proteins in neuro-degenerative diseases: diagnostic implications for Alzheimer’s disease and Lewy body dementias. Brain Pathol 3: 45–54PubMedCrossRefGoogle Scholar
  10. 10.
    Wischik CM, Novak M, Edwards PC, (1988) Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 85: 4884–4888PubMedCrossRefGoogle Scholar
  11. 11.
    Jicha GA, Berenfeld B, Davies P (1999) Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer’s disease. J Neurosci Res 55: 713–723PubMedCrossRefGoogle Scholar
  12. 12.
    Jicha GA, Bowser R, Kazam IG, (1997) Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J Neurosci Res 48: 128–132PubMedCrossRefGoogle Scholar
  13. 13.
    Jicha GA, Lane E, Vincent I, (1997) A conformation- and phosphorylation-dependent antibody recognizing the paired helical filaments of Alzheimer’s disease. J Neurochem 69: 2087–2095PubMedCrossRefGoogle Scholar
  14. 14.
    Luna-Muñoz J, García-Sierra F, Falcón V, (2005) Regional conformational change involving phosphorylation of tau protein at the Thr231, precedes the structural change detected by Alz-50 antibody in Alzheimer’s disease. J Alzheimers Dis 8: 29–41PubMedGoogle Scholar
  15. 15.
    Skrabana R, Kontsek P, Mederlyova A, (2004) Folding of Alzheimer’s core PHF subunit revealed by monoclonal antibody 423. FEBS Lett 568: 178–182PubMedCrossRefGoogle Scholar
  16. 16.
    Mena R, Wischik CM, Novak M, (1991) A progressive deposition of paired helical filaments (PHF) in the brain characterizes the evolution of dementia in Alzheimer’s disease. An immunocytochemical study with a monoclonal antibody against the PHF core. J Neuropathol Exp Neurol 50: 474–490Google Scholar
  17. 17.
    Fasulo L, Ugolini G, Visintin M, (2000) The neuronal microtubule-associated protein tau is a substrate for caspase-3 and an effector of apoptosis. J Neurochem 75: 624–633PubMedCrossRefGoogle Scholar
  18. 18.
    Gamblin TC, Berry RW, Binder LI (2003) Modeling tau polymerization in vitro: a review and synthesis. Biochemistry 42: 15009–15017PubMedCrossRefGoogle Scholar
  19. 19.
    Gamblin TC, Chen F, Zambrano A, (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 100: 10032–10037PubMedCrossRefGoogle Scholar
  20. 20.
    Guillozet-Bongaarts AL, Cahill ME, Cryns VL, (2006) Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J Neurochem 97: 1005–1014PubMedCrossRefGoogle Scholar
  21. 21.
    Guillozet-Bongaarts AL, Garcia-Sierra F, Reynolds MR, (2005) Tau truncation during neurofibrillary tangle evolution in Alzheimer’s disease. Neurobiol Aging 26: 1015–1022PubMedCrossRefGoogle Scholar
  22. 22.
    García-Sierra F, Ghoshal N, Quinn B, (2003) Conformational changes and truncation of tau protein during tangle evolution in Alzheimer’s disease. J Alzheimers Dis 5: 65–77PubMedGoogle Scholar
  23. 23.
    Bancher C, Brunner C, Lassmann H. (1989) Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res 477: 90–99PubMedCrossRefGoogle Scholar
  24. 24.
    Augustinack JC, Schneider A, Mandelkow EM, (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103: 26–35PubMedCrossRefGoogle Scholar
  25. 25.
    Luna-Muñoz J, Chávez-Macías L, García-Sierra F, (2007) Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J Alzheimers Dis 12: 365–375PubMedGoogle Scholar
  26. 26.
    Berry RW, Abraha A, Lagalwar S, (2003) Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment. Biochemistry 42: 8325–8331PubMedCrossRefGoogle Scholar
  27. 27.
    Gamblin TC, Berry RW, Binder LI (2003) Tau polymerization: role of the amino terminus. Biochemistry 42: 2252–2257PubMedCrossRefGoogle Scholar
  28. 28.
    Wischik CM, Edwards PC, Lai RY, (1995) Quantitative analysis of tau protein in paired helical filament preparations: implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer’s disease. Neurobiol Aging 16: 409–417PubMedCrossRefGoogle Scholar
  29. 29.
    Mena R, Edwards P, Pérez-Olvera O, (1995) Monitoring pathological assembly of tau and beta-amyloid proteins in Alzheimer’s disease. Acta Neuropathol 89: 50–56PubMedCrossRefGoogle Scholar
  30. 30.
    Mondragón-Rodríguez S, Basurto-Islas G, Santa-Maria I, (2008) Cleavage and conformational changes of tau protein follow phosphorylation during Alzheimer’s disease. Int J Exp Pathol 89: 81–90PubMedCrossRefGoogle Scholar
  31. 31.
    Carmel G, Mager EM, Binder LI, (1996) The structural basis of monoclonal antibody Alz50s selectivity for Alzheimer’s disease pathology. J Biol Chem 271: 32789–32795PubMedCrossRefGoogle Scholar
  32. 32.
    Uchihara T, Nakamura A, Yamazaki M, (2001) Evolution from pretangle neurons to neurofibrillary tangles monitored by thiazin red combined with Gallyas method and double immunofluorescence. Acta Neuropathol 101: 535–539PubMedGoogle Scholar
  33. 33.
    García-Sierra F, Wischik CM, Harrington CR, (2001) Accumulation of C-terminally truncated tau protein associated with vulnerability of the perforant pathway in early stages of neurofibrillary pathology in Alzheimer’s disease. J Chem Neuroanat 22: 65–77PubMedCrossRefGoogle Scholar
  34. 34.
    Novak M (1994) Truncated tau protein as a new marker for Alzheimer’s disease. Acta Virol 38: 173–189PubMedGoogle Scholar
  35. 35.
    Vincent I, Zheng JH, Dickson DW, (1998) Mitotic phosphoepitopes precede paired helical filaments in Alzheimer’s disease. Neurobiol Aging 19: 287–296PubMedCrossRefGoogle Scholar
  36. 36.
    Zheng-Fischhöfer Q, Biernat J, Mandelkow EM, (1998) Sequential phosphorylation of Tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specific epitope of antibody AT100 and requires a paired-helical-filament-like conformation. Eur J Biochem 252: 542–552PubMedCrossRefGoogle Scholar
  37. 37.
    Weaver CL, Espinoza M, Kress Y, (2000) Conformational change as one of the earliest alterations of tau in Alzheimer’s disease. Neurobiol Aging 21: 719–727PubMedCrossRefGoogle Scholar
  38. 38.
    Novak M, Wischik CM, Edwards P, (1989) Characterisation of the first monoclonal antibody against the pronase resistant core of the Alzheimer PHF. Prog Clin Biol Res 317: 755–761PubMedGoogle Scholar
  39. 39.
    Abraha A, Ghoshal N, Gamblin TC, (2000) C-terminal inhibition of tau assembly in vitro and in Alzheimer’s disease. J Cell Sci 113 Pt. 21: 3737–3745Google Scholar
  40. 40.
    Galván M, David JP, Delacourte A, (2001) Sequence of neurofibrillary changes in aging and Alzheimer’s disease: a confocal study with phospho-tau antibody, AD2. J Alzheimers Dis 3: 417–425PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Physiology and NeurosciencesCenter of Research and Advanced StudiesMexico

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