Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1995 Apr 3;14(7):1304–1313. doi: 10.1002/j.1460-2075.1995.tb07116.x

Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform.

J Götz 1, A Probst 1, M G Spillantini 1, T Schäfer 1, R Jakes 1, K Bürki 1, M Goedert 1
PMCID: PMC398215  PMID: 7729409

Abstract

Microtubule-associated protein tau is the major constituent of the paired helical filament, the main fibrous component of the neurofibrillary lesions of Alzheimer's disease. Tau is an axonal phosphoprotein in normal adult brain. In Alzheimer's disease brain tau is hyperphosphorylated and is found not only in axons, but also in cell bodies and dendrites of affected nerve cells. We report the production and analysis of transgenic mice that express the longest human brain tau isoform under the control of the human Thy-1 promoter. As in Alzheimer's disease, transgenic human tau protein was present in nerve cell bodies, axons and dendrites; moreover, it was phosphorylated at sites that are hyperphosphorylated in paired helical filaments. We conclude that transgenic human tau protein showed pre-tangle changes similar to those that precede the full neurofibrillary pathology in Alzheimer's disease.

Full text

PDF
1308

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bancher C., Brunner C., Lassmann H., Budka H., Jellinger K., Wiche G., Seitelberger F., Grundke-Iqbal I., Iqbal K., Wisniewski H. M. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 1989 Jan 16;477(1-2):90–99. doi: 10.1016/0006-8993(89)91396-6. [DOI] [PubMed] [Google Scholar]
  2. Baumann K., Mandelkow E. M., Biernat J., Piwnica-Worms H., Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 1993 Dec 28;336(3):417–424. doi: 10.1016/0014-5793(93)80849-p. [DOI] [PubMed] [Google Scholar]
  3. Beaudet L., Charron G., Houle D., Tretjakoff I., Peterson A., Julien J. P. Intragenic regulatory elements contribute to transcriptional control of the neurofilament light gene. Gene. 1992 Jul 15;116(2):205–214. doi: 10.1016/0378-1119(92)90517-s. [DOI] [PubMed] [Google Scholar]
  4. Binder L. I., Frankfurter A., Rebhun L. I. The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985 Oct;101(4):1371–1378. doi: 10.1083/jcb.101.4.1371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boehm T., Greenberg J. M., Buluwela L., Lavenir I., Forster A., Rabbitts T. H. An unusual structure of a putative T cell oncogene which allows production of similar proteins from distinct mRNAs. EMBO J. 1990 Mar;9(3):857–868. doi: 10.1002/j.1460-2075.1990.tb08183.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Braak E., Braak H., Mandelkow E. M. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol. 1994;87(6):554–567. doi: 10.1007/BF00293315. [DOI] [PubMed] [Google Scholar]
  7. Bramblett G. T., Goedert M., Jakes R., Merrick S. E., Trojanowski J. Q., Lee V. M. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron. 1993 Jun;10(6):1089–1099. doi: 10.1016/0896-6273(93)90057-x. [DOI] [PubMed] [Google Scholar]
  8. Brion J. P., Smith C., Couck A. M., Gallo J. M., Anderton B. H. Developmental changes in tau phosphorylation: fetal tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer's disease. J Neurochem. 1993 Dec;61(6):2071–2080. doi: 10.1111/j.1471-4159.1993.tb07444.x. [DOI] [PubMed] [Google Scholar]
  9. Cattoretti G., Pileri S., Parravicini C., Becker M. H., Poggi S., Bifulco C., Key G., D'Amato L., Sabattini E., Feudale E. Antigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J Pathol. 1993 Oct;171(2):83–98. doi: 10.1002/path.1711710205. [DOI] [PubMed] [Google Scholar]
  10. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  11. Cleveland D. W., Hwo S. Y., Kirschner M. W. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol. 1977 Oct 25;116(2):207–225. doi: 10.1016/0022-2836(77)90213-3. [DOI] [PubMed] [Google Scholar]
  12. Drewes G., Lichtenberg-Kraag B., Döring F., Mandelkow E. M., Biernat J., Goris J., Dorée M., Mandelkow E. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 1992 Jun;11(6):2131–2138. doi: 10.1002/j.1460-2075.1992.tb05272.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gallyas F. Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morphol Acad Sci Hung. 1971;19(1):1–8. [PubMed] [Google Scholar]
  14. Goedert M., Cohen E. S., Jakes R., Cohen P. p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. FEBS Lett. 1992 Nov 2;312(1):95–99. doi: 10.1016/0014-5793(92)81418-l. [DOI] [PubMed] [Google Scholar]
  15. Goedert M., Jakes R., Crowther R. A., Cohen P., Vanmechelen E., Vandermeeren M., Cras P. Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: identification of phosphorylation sites in tau protein. Biochem J. 1994 Aug 1;301(Pt 3):871–877. doi: 10.1042/bj3010871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goedert M., Jakes R., Crowther R. A., Six J., Lübke U., Vandermeeren M., Cras P., Trojanowski J. Q., Lee V. M. The abnormal phosphorylation of tau protein at Ser-202 in Alzheimer disease recapitulates phosphorylation during development. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5066–5070. doi: 10.1073/pnas.90.11.5066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Goedert M., Jakes R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 1990 Dec;9(13):4225–4230. doi: 10.1002/j.1460-2075.1990.tb07870.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Goedert M., Spillantini M. G., Cairns N. J., Crowther R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992 Jan;8(1):159–168. doi: 10.1016/0896-6273(92)90117-v. [DOI] [PubMed] [Google Scholar]
  19. Goedert M., Spillantini M. G., Jakes R., Rutherford D., Crowther R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. 1989 Oct;3(4):519–526. doi: 10.1016/0896-6273(89)90210-9. [DOI] [PubMed] [Google Scholar]
  20. Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 1993 Nov;16(11):460–465. doi: 10.1016/0166-2236(93)90078-z. [DOI] [PubMed] [Google Scholar]
  21. Greenberg J. M., Boehm T., Sofroniew M. V., Keynes R. J., Barton S. C., Norris M. L., Surani M. A., Spillantini M. G., Rabbitts T. H. Segmental and developmental regulation of a presumptive T-cell oncogene in the central nervous system. Nature. 1990 Mar 8;344(6262):158–160. doi: 10.1038/344158a0. [DOI] [PubMed] [Google Scholar]
  22. Greenberg S. G., Davies P. A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5827–5831. doi: 10.1073/pnas.87.15.5827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Greenberg S. G., Davies P., Schein J. D., Binder L. I. Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. J Biol Chem. 1992 Jan 5;267(1):564–569. [PubMed] [Google Scholar]
  24. Hanger D. P., Hughes K., Woodgett J. R., Brion J. P., Anderton B. H. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett. 1992 Nov 23;147(1):58–62. doi: 10.1016/0304-3940(92)90774-2. [DOI] [PubMed] [Google Scholar]
  25. Hasegawa M., Morishima-Kawashima M., Takio K., Suzuki M., Titani K., Ihara Y. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J Biol Chem. 1992 Aug 25;267(24):17047–17054. [PubMed] [Google Scholar]
  26. Hasegawa M., Watanabe A., Takio K., Suzuki M., Arai T., Titani K., Ihara Y. Characterization of two distinct monoclonal antibodies to paired helical filaments: further evidence for fetal-type phosphorylation of the tau in paired helical filaments. J Neurochem. 1993 Jun;60(6):2068–2077. doi: 10.1111/j.1471-4159.1993.tb03491.x. [DOI] [PubMed] [Google Scholar]
  27. Higgins L. S., Holtzman D. M., Rabin J., Mobley W. C., Cordell B. Transgenic mouse brain histopathology resembles early Alzheimer's disease. Ann Neurol. 1994 May;35(5):598–607. doi: 10.1002/ana.410350514. [DOI] [PubMed] [Google Scholar]
  28. Ishiguro K., Shiratsuchi A., Sato S., Omori A., Arioka M., Kobayashi S., Uchida T., Imahori K. Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett. 1993 Jul 5;325(3):167–172. doi: 10.1016/0014-5793(93)81066-9. [DOI] [PubMed] [Google Scholar]
  29. Kenessey A., Yen S. H. The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments. Brain Res. 1993 Nov 26;629(1):40–46. doi: 10.1016/0006-8993(93)90478-6. [DOI] [PubMed] [Google Scholar]
  30. Kobayashi S., Ishiguro K., Omori A., Takamatsu M., Arioka M., Imahori K., Uchida T. A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule. FEBS Lett. 1993 Dec 6;335(2):171–175. doi: 10.1016/0014-5793(93)80723-8. [DOI] [PubMed] [Google Scholar]
  31. Kosik K. S., Orecchio L. D., Binder L., Trojanowski J. Q., Lee V. M., Lee G. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron. 1988 Nov;1(9):817–825. doi: 10.1016/0896-6273(88)90129-8. [DOI] [PubMed] [Google Scholar]
  32. Kozak M. An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 1987 Oct 26;15(20):8125–8148. doi: 10.1093/nar/15.20.8125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lamb B. T., Sisodia S. S., Lawler A. M., Slunt H. H., Kitt C. A., Kearns W. G., Pearson P. L., Price D. L., Gearhart J. D. Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected]. Nat Genet. 1993 Sep;5(1):22–30. doi: 10.1038/ng0993-22. [DOI] [PubMed] [Google Scholar]
  34. Lang E., Szendrei G. I., Lee V. M., Otvos L., Jr Immunological and conformation characterization of a phosphorylated immunodominant epitope on the paired helical filaments found in Alzheimer's disease. Biochem Biophys Res Commun. 1992 Sep 16;187(2):783–790. doi: 10.1016/0006-291x(92)91264-q. [DOI] [PubMed] [Google Scholar]
  35. Lee V. M., Balin B. J., Otvos L., Jr, Trojanowski J. Q. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science. 1991 Feb 8;251(4994):675–678. doi: 10.1126/science.1899488. [DOI] [PubMed] [Google Scholar]
  36. Liu W. K., Dickson D. W., Yen S. H. Heterogeneity of tau proteins in Alzheimer's disease. Evidence for increased expression of an isoform and preferential distribution of a phosphorylated isoform in neurites. Am J Pathol. 1993 Feb;142(2):387–394. [PMC free article] [PubMed] [Google Scholar]
  37. Mandelkow E. M., Drewes G., Biernat J., Gustke N., Van Lint J., Vandenheede J. R., Mandelkow E. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 1992 Dec 21;314(3):315–321. doi: 10.1016/0014-5793(92)81496-9. [DOI] [PubMed] [Google Scholar]
  38. Mercken M., Vandermeeren M., Lübke U., Six J., Boons J., Van de Voorde A., Martin J. J., Gheuens J. Monoclonal antibodies with selective specificity for Alzheimer Tau are directed against phosphatase-sensitive epitopes. Acta Neuropathol. 1992;84(3):265–272. doi: 10.1007/BF00227819. [DOI] [PubMed] [Google Scholar]
  39. Otvos L., Jr, Feiner L., Lang E., Szendrei G. I., Goedert M., Lee V. M. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404. J Neurosci Res. 1994 Dec 15;39(6):669–673. doi: 10.1002/jnr.490390607. [DOI] [PubMed] [Google Scholar]
  40. Oyama F., Cairns N. J., Shimada H., Oyama R., Titani K., Ihara Y. Down's syndrome: up-regulation of beta-amyloid protein precursor and tau mRNAs and their defective coordination. J Neurochem. 1994 Mar;62(3):1062–1066. doi: 10.1046/j.1471-4159.1994.62031062.x. [DOI] [PubMed] [Google Scholar]
  41. Paudel H. K., Lew J., Ali Z., Wang J. H. Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments. J Biol Chem. 1993 Nov 5;268(31):23512–23518. [PubMed] [Google Scholar]
  42. Peng I., Binder L. I., Black M. M. Biochemical and immunological analyses of cytoskeletal domains of neurons. J Cell Biol. 1986 Jan;102(1):252–262. doi: 10.1083/jcb.102.1.252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pircher H., Mak T. W., Lang R., Ballhausen W., Rüedi E., Hengartner H., Zinkernagel R. M., Bürki K. T cell tolerance to Mlsa encoded antigens in T cell receptor V beta 8.1 chain transgenic mice. EMBO J. 1989 Mar;8(3):719–727. doi: 10.1002/j.1460-2075.1989.tb03431.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Quon D., Wang Y., Catalano R., Scardina J. M., Murakami K., Cordell B. Formation of beta-amyloid protein deposits in brains of transgenic mice. Nature. 1991 Jul 18;352(6332):239–241. doi: 10.1038/352239a0. [DOI] [PubMed] [Google Scholar]
  45. Sakimura K., Kushiya E., Takahashi Y., Suzuki Y. The structure and expression of neuron-specific enolase gene. Gene. 1987;60(1):103–113. doi: 10.1016/0378-1119(87)90218-6. [DOI] [PubMed] [Google Scholar]
  46. Schmidt M. L., DiDario A. G., Lee V. M., Trojanowski J. Q. An extensive network of PHF tau-rich dystrophic neurites permeates neocortex and nearly all neuritic and diffuse amyloid plaques in Alzheimer disease. FEBS Lett. 1994 May 9;344(1):69–73. doi: 10.1016/0014-5793(94)00259-2. [DOI] [PubMed] [Google Scholar]
  47. Seki T., Spurr N., Obata F., Goyert S., Goodfellow P., Silver J. The human Thy-1 gene: structure and chromosomal location. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6657–6661. doi: 10.1073/pnas.82.19.6657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Trojanowski J. Q., Schuck T., Schmidt M. L., Lee V. M. Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem. 1989 Feb;37(2):209–215. doi: 10.1177/37.2.2492045. [DOI] [PubMed] [Google Scholar]
  49. Watanabe A., Hasegawa M., Suzuki M., Takio K., Morishima-Kawashima M., Titani K., Arai T., Kosik K. S., Ihara Y. In vivo phosphorylation sites in fetal and adult rat tau. J Biol Chem. 1993 Dec 5;268(34):25712–25717. [PubMed] [Google Scholar]
  50. Yoshida H., Ihara Y. Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. J Neurochem. 1993 Sep;61(3):1183–1186. doi: 10.1111/j.1471-4159.1993.tb03642.x. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES