Acta Neuropathologica

, Volume 80, Issue 2, pp 111–117 | Cite as

Pathological proteins Tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer's disease

Demonstration with a panel of antibodies against Tau proteins
  • A. Delacourte
  • S. Flament
  • E. M. Dibe
  • P. Hublau
  • P. Sablnnière
  • B. Hémon
  • V. Shérrer
  • A. Défossez
Regular Papers


Bundles of paired helical filaments (PHF) accumulate in the pyramidal neurons that degenerate during Alzheimer's disease. This neurofibrillary degeneration is highly correlated with clinical signs of dementia. During the degenerating process, Tau proteins, which are the major antigenic components of PHF, are abnormally phosphorylated and two pathological isoforms named Tau 64 and 69 are expressed. We have studied their immunoblot distribution in the cortical gray and white matter from different regions of normal and Alzheimer brains, to determine if the degenerating process preferentially affects the somatodendritic or the axonal domain. Two categories of antibodies were used. The first category consisted of anti-human native Tau, anti-Tau proteins from different vertebrates, anti-PHF, monoclonal antibody Alz-50 and an anti-C terminal repeated region of Tau. In control brains, these antibodies strongly detected normal Tau proteins in the gray matter while Tau immunodetection was weak in the white matter. In Alzheimer brain cortices, each antibody detected Tau 64 and 69 in gray matter extracts but not at all in white matter extracts. The second category of anti-Tau consisted of the anti-PHF saturated with normal brain protein extracts. This antiserum only probed the abnormally phosphorylated Tau proteins. It detected Tau 64 and 69 exclusively in the cortical gray matter of Alzheimer brains. Moreover, a 55-kDa Tau protein was also immunolabelled, which might be an intermediary form between normal Tau and Tau 64 and 69. Our results demonstrate that Tau proteins are normal and major components of the somatodendritic domain and that Tau pathology, reflected by the presence of Tau 64 and 69, affects preferentially this domain during Alzheimer's disease.

Key words

Alzheimer's disease Tau proteins Phosphorylation Neurofibrillary degeneration Paired helical filaments 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Baudier J, Cole RD (1987) Phosphorylation of Tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J Biol Chem 262:17577–17583Google Scholar
  2. 2.
    Behrouz N, Défossez A, Delacourte A, Hublau P, Mazzuca M (1990) Alzheimer's disease: glycolytic pretreatment enhances dramatically the immunolabelling of senile plaques and cerebrovascular amyloid substance. Lab Invest 61:576–583Google Scholar
  3. 3.
    Binder L, Frankfurter A, Rebhun L (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101:1371–1378Google Scholar
  4. 4.
    Brion JP, Passareiro H, Nunez J, Flament-Durand J (1985) Mise en evidence immunologique de la proteine Tau au niveau de lesions de degenerescence neurofibrillaire de la maladie d'Alzheimer. Arch Neurol 95:229–235Google Scholar
  5. 5.
    Brion JP, Guillemot J, Couchie D, Flament-Durand J, Nunez J (1988) Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing fetal and adult rat cerebellum. Neuroscience 25:139–146Google Scholar
  6. 6.
    Buée L, Laine A, Delacourte A, Flament S, Han KK (1989) Qualitative and quantitative comparison of brain proteins in Alzheimer's disease. Biol Chem Hoppe-Seyler 370:1229–1234Google Scholar
  7. 7.
    Chedid L, Jolivet M, Audibert F, Przewlocki G, Beachey EH, Gras Masse H, Tartar A (1983) Antibody responses elicited by a polyvalent vaccine containing synthetic diphterra, streptococcal and hepatitis peptides coupled to the same carrier. Biochem Biophys Res Commun 117:908–912Google Scholar
  8. 8.
    Crowther T, Goedert M, Wischik CM (1989) The repeat region of microtubule-associated protein Tau forms part of the core of the paired helical filaments of Alzheimer's disease. Ann Med 21:127–132Google Scholar
  9. 9.
    Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, Masters C (1988) A4 amyloid protein deposition and the diagnosis of Alzheimer's disease. Prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38:1688–1893Google Scholar
  10. 10.
    Davies P (1989) A different view of A68 and amyloid. Neurobiol Aging 10:408–409Google Scholar
  11. 11.
    Delaere P, Duyckaerts C, Brion J-P, Poulain V, Hauw J-J (1989) Tau, paired helical filaments and amyloid in the neocortex: a morphometric study of 15 cases with graded intellectual status in aging and senile dementia of Alzheimer's type. Acta Neuropathol 77:645–653Google Scholar
  12. 12.
    Defossez A, Beauvillain J-C, Delacourte A, Mazzuca M (1988) Alzheimer's disease: a new evidence for common epitopes between microtubule associated protein tau and paired helical filaments (PHF): demonstration at the electron microscope by a double immunogold labelling. Virchows Arch [A] 413:141–145Google Scholar
  13. 13.
    Delacourte A, Défossez A (1986) Alzheimer's disease: tau proteins, the promoting factors of microtubule assembly, are major antigenic components of paired helical filaments. J Neurol Sci 76:173–186Google Scholar
  14. 14.
    Delacourte A, Défossez A (1988) Paired helical filaments in Alzheimer's disease: their formation and their transformation.—In: Pouplar-Barthelaix A, Emile J, Christen Y (eds) Immunological aspects of Alzheimer's disease. Springer Verlag, Heidelberg, pp 55–67Google Scholar
  15. 15.
    Delacourte A, Hémon B, Verleye M, Keyser L, Han K-K, Défossez A (1988) Tau proteins are major components of the somatodendritic domain of the human brain. Study in normal and Alzheimer brains. In: Rousset B (ed) European symposium on the structure and functions of the cytoskeleton, Colloque INSERM, vol 171. John Libbey Eurotext, London Paris, pp 225–230Google Scholar
  16. 16.
    Delacourte A, Flament S, Défossez A (1989) Tau 64 and 69 are early biochemical markers of the neurofibrillary degeneration: implications for the diagnosis and the in vitro study of the neurodegenerative process. Clin Neuropathol 8:225Google Scholar
  17. 17.
    Delacourte A, Flament S, Défossez A, Buée L, Hémon B, Parent M, Furby A, Leys D, Goudemand M, Destée A, Petit H (1989) Tau 64 and 69: two early biochemical markers of the neurofibrillary degeneration. In: Boller F, Katzmann R, Rascol A, Signoret J-L, Christen Y (eds) Colloques médecine et recherche: biological markers of Alzheimer's disease. Springer Verlag, Berlin Paris, pp 39–55Google Scholar
  18. 18.
    Delacourte A, Flament S, Défossez A (1989) Vers la mise au point d'un modèle d'étude in vitro de la dégénérescence neurofibrillaire de type Alzheimer. Presse Med 19:170–173Google Scholar
  19. 19.
    Duyckaerts C, Hauw JJ, Piette I, Rainsard C, Poulain V, Berthaux P, Escourolle R (1985) Cortical atrophy in senile dementia of the Alzheimer type is mainly due to a decrease in cortical length. Acta Neuropathol (Berl) 66:72–74Google Scholar
  20. 20.
    Duyckaerts C, Delaere P, Poulain V, Brion J-P, Hauw J-J (1988) Does amyloid precede “PHF” in the senile plaque? A study of 15 cases with graded intellectual status in aging and AD. Neurosci Lett 91:354–359Google Scholar
  21. 21.
    Flament S, Delacourte A (1989) Abnormal Tau species are produced during Alzheimer's disease neurodegenerative process. FEBS Lett 247:213–216Google Scholar
  22. 22.
    Flament S, Delacourte A, Hémon B, Défossez A (1989) Characterization of two pathological Tau variants in Alzheimer brain cortices. J Neurol Sci 92:133–141Google Scholar
  23. 23.
    Flament S, Delacourte A, Mann DMA (1990) Phosphorylation of Tau proteins: a major event during the process of neurofibrillary degeneration. A comparative study between Alzheimer's disease and Down's syndrome. Brain Res (in press)Google Scholar
  24. 24.
    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 messenger RNAs in human brain. EMBO J 8:393–399Google Scholar
  25. 25.
    Hansen LA, Deters AR, Davies P, Terry RD (1988) Neocortical morphometry, lesion counts, and choline acetyltransferase levels in the age spectrum of Alzheimer's disease. Neurology 38:48–54Google Scholar
  26. 26.
    Kidd H (1964) Alzheimer's disease. An electron microscopical study. Brain 87:307–320Google Scholar
  27. 27.
    Kondo J, Honda T, Mori H, Hamada Y, Miura R, Ogawara M, Ihara Y (1988) The carboxyl third of Tau is tighly bound to paired helical filaments. Neuron 1:827–834Google Scholar
  28. 28.
    Kosik KS, Finch EA (1987) MAP 2 and Tau segregate into dendritic and axonal domains after the elaboration of morphological distinct neurites: an immunocytochemical study of cultured rat cerebrum. J Neurosci 7:3142–3153Google Scholar
  29. 29.
    Kosik KS, Crandall JE, Mufson EJ, Neve RL (1989) Tau: in situ hybridization in normal and alzheimer brain — Localization in the somatodendritic compartment. Ann Neurol 26:352–361Google Scholar
  30. 30.
    Kowall NW, Kosik KS (1987) Axonal disruption and aberrant localization of Tau protein characterize the neuropil pathology of Alzheimer's disease. Ann Neurol 22:639–643Google Scholar
  31. 31.
    Ksiezak-Reding H, Davies P, Yen SY (1988) Alz-50, a monoclonal antibody to Alzheimer's disease antigen, cross-reacts with Tau proteins from bovine and normal human brain. J Biol Chem 263:7943–7947Google Scholar
  32. 32.
    Laemmli UK (1970) Cleavage of structural proteins during head assembly of bacteriophage T4. Nature 227:680–685Google Scholar
  33. 33.
    Lewis SA, Wang D, Cowan NJ (1988) Microtubule-associated protein, MAP2, shares a similar microtubule binding motif tau. Science 242:936–939Google Scholar
  34. 34.
    Mandybur TI (1989) Cerebral amyloid angiopathy and astrocytic gliosis in Alzheimer's disease. Acta Neuropathol 78:329–331Google Scholar
  35. 35.
    Mann DMA, Tucker CM, Yates PO (1987) The topographical distribution of senile plaques and neurofibrillary tangles in the brain of non-demented persons of different ages. Neuropathol Appl Neurobiol 13:123–127Google Scholar
  36. 36.
    McKhann GD, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of department of health and human services task force on Alzheimer's disease. Neurology 34:939–944Google Scholar
  37. 37.
    Merrifield RB (1963) Solid phase peptide synthesis: the synthesis of a tetrapeptide. J Am Chem soc 83:2149–2153Google Scholar
  38. 38.
    Nukina N, Kosik KS, Selkoe DJ (1988) The monoclonal antibody, Alz-50, recognizes Tau proteins in Alzheimer's disease brain. Neurosci Lett 87:240–246Google Scholar
  39. 39.
    O'Farrell PH (1975) High-resolution two-dimensional electrophoresis of proteins. J Biol Chem 250:4007–4021Google Scholar
  40. 40.
    Papasozomenos SCH, Binder LI (1987) Phosphorylation determines two distinct species of Tau in the central nervous system. Cell Motil Cytoskel 8:210–226Google Scholar
  41. 41.
    Parent M, Delacourte A, Défossez A, Hemon B, Han KK, Petit H (1988) Alzheimer's disease: study of the distribution of paired helical filaments tau proteins in the human central nervous system. C R Acad Sci (Paris) 306:391–397Google Scholar
  42. 42.
    Rosenblatt M, Fellous A, Mazié JC, Delacourte A, Défossez A (1989) Alzheimer's disease: microtubule-associated proteins 2 (MAP2) are not components of paired helical filaments. FEBS Lett 252:91–94Google Scholar
  43. 43.
    Sumpter PQ, Mann DMA, Davies CA, Yates PO, Snowden JS, Neary D (1986) A quantitative study of the ultrustructure of pyramidal neurons of the cerebral cortex in Alzheimer disease in relationship to the degree of dementia. Neuropathol Appl Neurobiol 12:321–329Google Scholar
  44. 44.
    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's disease. Proc Natl Acad Sci USA 85:4506–4510Google Scholar
  45. 45.
    Wolozin BL, Pruchniki A, Dickson DW, Davies P (1986) A neuronal antigen in the brains of Alzheimer patients. Science 232:648–650Google Scholar
  46. 46.
    Wood JG, Mirra SS, Pollock NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer's disease share antigenic determinants with the axonal microtubule-associated protein tau. Proc Natl Acad Sci USA 83:404–4043Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • A. Delacourte
    • 1
  • S. Flament
    • 1
  • E. M. Dibe
    • 1
  • P. Hublau
    • 1
  • P. Sablnnière
    • 1
  • B. Hémon
    • 1
  • V. Shérrer
    • 1
  • A. Défossez
    • 1
  1. 1.Unité INSERM 156, Faculté de Médecine de LilleA.D.E.R.M.A.Lille CédexFrance

Personalised recommendations