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. 1989 Jul;86(14):5646–5650. doi: 10.1073/pnas.86.14.5646

Identification and localization of a tau peptide to paired helical filaments of Alzheimer disease.

K Iqbal 1, I Grundke-Iqbal 1, A J Smith 1, L George 1, Y C Tung 1, T Zaidi 1
PMCID: PMC297681  PMID: 2501795

Abstract

Amino acid sequencing of a CNBr digest of the tau protein isolated from bovine brain revealed an amino acid sequence of 17 residues, Pro-Gly-Leu-Lys-Glu-Ser-Pro-Leu-Gln-Ile-Gly-Ala-Ala-Pro-Gly-Leu-Lys, which we call peptide I, with heterogeneity at position 11 of glycine (peptide Ia) and proline (peptide Ib); peptide I showed no homology with the previously reported cDNA-derived mouse and human tau sequences. Antisera raised to synthetic peptides corresponding to peptides Ia and Ib labeled all the bovine tau polypeptides recognized by other monoclonal and polyclonal antibodies to bovine tau. Antisera to peptide Ib did not label any mouse tau polypeptides; however, an anti-Ia antiserum labeled two of the four mouse tau polypeptides. Antisera to both peptides labeled paired helical filaments (PHF) as neurofibrillary tangles, plaque neurites, and neuropil threads in Alzheimer disease brain and PHF polypeptides on immunoblots. Immunostaining with anti-Ia antisera of PHF in tissue sections and PHF polypeptides, but not bovine tau, on immunoblots was markedly increased when pretreated with alkaline phosphatase. These studies suggest that (i) the amino acid sequences of some isoforms of tau peptide might be different from that predicted from cDNAs, (ii) a tau peptide that is absent in the predicted sequences is present in PHF in Alzheimer disease, and (iii) tau in PHF is abnormally phosphorylated.

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Selected References

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

  1. Baudier J., Cole R. D. 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. 1987 Dec 25;262(36):17577–17583. [PubMed] [Google Scholar]
  2. Baudier J., Lee S. H., Cole R. D. Separation of the different microtubule-associated tau protein species from bovine brain and their mode II phosphorylation by Ca2+/phospholipid-dependent protein kinase C. J Biol Chem. 1987 Dec 25;262(36):17584–17590. [PubMed] [Google Scholar]
  3. 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]
  4. Braak H., Braak E., Grundke-Iqbal I., Iqbal K. Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett. 1986 Apr 24;65(3):351–355. doi: 10.1016/0304-3940(86)90288-0. [DOI] [PubMed] [Google Scholar]
  5. Cleveland D. W., Hwo S. Y., Kirschner M. W. Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol. 1977 Oct 25;116(2):227–247. doi: 10.1016/0022-2836(77)90214-5. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Drubin D. G., Kirschner M. W. Tau protein function in living cells. J Cell Biol. 1986 Dec;103(6 Pt 2):2739–2746. doi: 10.1083/jcb.103.6.2739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Goedert M., Spillantini M. G., Potier M. C., Ulrich J., Crowther R. A. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 1989 Feb;8(2):393–399. doi: 10.1002/j.1460-2075.1989.tb03390.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goedert M., Wischik C. M., Crowther R. A., Walker J. E., Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988 Jun;85(11):4051–4055. doi: 10.1073/pnas.85.11.4051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grundke-Iqbal I., Iqbal K., Quinlan M., Tung Y. C., Zaidi M. S., Wisniewski H. M. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986 May 5;261(13):6084–6089. [PubMed] [Google Scholar]
  11. Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., Binder L. I. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4913–4917. doi: 10.1073/pnas.83.13.4913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Grundke-Iqbal I., Iqbal K., Tung Y. C., Wang G. P., Wisniewski H. M. Alzheimer paired helical filaments: cross-reacting polypeptide/s normally present in brain. Acta Neuropathol. 1985;66(1):52–61. doi: 10.1007/BF00698295. [DOI] [PubMed] [Google Scholar]
  13. Grundke-Iqbal I., Iqbal K., Tung Y. C., Wisniewski H. M. Alzheimer paired helical filaments: immunochemical identification of polypeptides. Acta Neuropathol. 1984;62(4):259–267. doi: 10.1007/BF00687607. [DOI] [PubMed] [Google Scholar]
  14. Grundke-Iqbal I., Johnson A. B., Terry R. D., Wisniewski H. M., Iqbal K. Alzheimer neurofibrillary tangles: antiserum and immunohistological staining. Ann Neurol. 1979 Dec;6(6):532–537. doi: 10.1002/ana.410060612. [DOI] [PubMed] [Google Scholar]
  15. Grundke-Iqbal I., Johnson A. B., Wisniewski H. M., Terry R. D., Iqbal K. Evidence that Alzheimer neurofibrillary tangles originate from neurotubules. Lancet. 1979 Mar 17;1(8116):578–580. doi: 10.1016/s0140-6736(79)91006-7. [DOI] [PubMed] [Google Scholar]
  16. Grundke-Iqbal I., Vorbrodt A. W., Iqbal K., Tung Y. C., Wang G. P., Wisniewski H. M. Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. Brain Res. 1988 Aug;464(1):43–52. doi: 10.1016/0169-328x(88)90017-4. [DOI] [PubMed] [Google Scholar]
  17. Himmler A., Drechsel D., Kirschner M. W., Martin D. W., Jr Tau consists of a set of proteins with repeated C-terminal microtubule-binding domains and variable N-terminal domains. Mol Cell Biol. 1989 Apr;9(4):1381–1388. doi: 10.1128/mcb.9.4.1381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ihara Y., Nukina N., Miura R., Ogawara M. Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer's disease. J Biochem. 1986 Jun;99(6):1807–1810. doi: 10.1093/oxfordjournals.jbchem.a135662. [DOI] [PubMed] [Google Scholar]
  19. Iqbal K., Grundke-Iqbal I., Zaidi T., Merz P. A., Wen G. Y., Shaikh S. S., Wisniewski H. M., Alafuzoff I., Winblad B. Defective brain microtubule assembly in Alzheimer's disease. Lancet. 1986 Aug 23;2(8504):421–426. doi: 10.1016/s0140-6736(86)92134-3. [DOI] [PubMed] [Google Scholar]
  20. Iqbal K., Smith A. J., Zaidi T., Grundke-Iqbal I. Microtubule-associated protein tau. Identification of a novel peptide from bovine brain. FEBS Lett. 1989 May 8;248(1-2):87–91. doi: 10.1016/0014-5793(89)80437-5. [DOI] [PubMed] [Google Scholar]
  21. Iqbal K., Wiśniewski H. M., Shelanski M. L., Brostoff S., Liwnicz B. H., Terry R. D. Protein changes in senile dementia. Brain Res. 1974 Sep 6;77(2):337–343. doi: 10.1016/0006-8993(74)90798-7. [DOI] [PubMed] [Google Scholar]
  22. Iqbal K., Zaidi T., Thompson C. H., Merz P. A., Wisniewski H. M. Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition. Acta Neuropathol. 1984;62(3):167–177. doi: 10.1007/BF00691849. [DOI] [PubMed] [Google Scholar]
  23. Ksiezak-Reding H., Binder L. I., Yen S. H. Immunochemical and biochemical characterization of tau proteins in normal and Alzheimer's disease brains with Alz 50 and Tau-1. J Biol Chem. 1988 Jun 15;263(17):7948–7953. [PubMed] [Google Scholar]
  24. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  25. Lee G., Cowan N., Kirschner M. The primary structure and heterogeneity of tau protein from mouse brain. Science. 1988 Jan 15;239(4837):285–288. doi: 10.1126/science.3122323. [DOI] [PubMed] [Google Scholar]
  26. Lindwall G., Cole R. D. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem. 1984 Apr 25;259(8):5301–5305. [PubMed] [Google Scholar]
  27. Lindwall G., Cole R. D. The purification of tau protein and the occurrence of two phosphorylation states of tau in brain. J Biol Chem. 1984 Oct 10;259(19):12241–12245. [PubMed] [Google Scholar]
  28. Papasozomenos S. C., Binder L. I. Phosphorylation determines two distinct species of Tau in the central nervous system. Cell Motil Cytoskeleton. 1987;8(3):210–226. doi: 10.1002/cm.970080303. [DOI] [PubMed] [Google Scholar]
  29. Shelanski M. L., Gaskin F., Cantor C. R. Microtubule assembly in the absence of added nucleotides. Proc Natl Acad Sci U S A. 1973 Mar;70(3):765–768. doi: 10.1073/pnas.70.3.765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Weingarten M. D., Lockwood A. H., Hwo S. Y., Kirschner M. W. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975 May;72(5):1858–1862. doi: 10.1073/pnas.72.5.1858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wischik C. M., Novak M., Thøgersen H. C., Edwards P. C., Runswick M. J., Jakes R., Walker J. E., Milstein C., Roth M., Klug A. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4506–4510. doi: 10.1073/pnas.85.12.4506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wood J. G., Mirra S. S., Pollock N. J., Binder L. I. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau) Proc Natl Acad Sci U S A. 1986 Jun;83(11):4040–4043. doi: 10.1073/pnas.83.11.4040. [DOI] [PMC free article] [PubMed] [Google Scholar]

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