Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which abnormal filamentous inclusions accumulate in dystrophic and dying nerve cells. These inclusions have been described as neurofibrillary tangles (NFTs) of which paired helical filaments (PHFs) are the primary constituents (1-3). The PHFs primarily are composed of the microtubule-associated protein tau, which has undergone posttranslational modification such as phosphorylation (4,5), glycation (6-9), and crosslinking by transglutaminase (TGase) (10-16). Crosslinking of proteins catalyzed by TGase results in the deposition of these proteins into insoluble matrices that are resistant to proteolytic digestion and chaotropic denaturation (for review see ref. 17). In this regard, TGase has been demonstrated to be associated with NFTs from the Alzheimer brain (13,14) and to exhibit elevated activity in the AD brain as compared with normal aged-matched control subjects (16). Here we discuss important aspects of TGase and in vitro experimental approaches that address its ability to catalyze the tau protein into insoluble complexes exhibiting biophysical and immuno-logical properties similar to those of the Alzheimer PHFs and NFTs.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Kidd, M. (1963) Paired helical filaments in electron microscopy of Alzheimer’s disease. Nature 197, 192–193.
Terry, R. D., Gonatas, N. K., and Weiss, M. (1964) Ultrastructural studies in Alzheimer’s presenile dementia. Am. J. Pathol. 44, 269–297.
Wisniewski, H. M., Narang, H. K., and Terry, R. D. (1976) Neurofibrillary tangles of paired helical filaments. J. Neurol. Sci. 27,173–181.
Greenberg, S. G. and Davies, P. (1990) A preparation of Alzheimer paired helical filaments that displays distinct tau-proteins by polyacrylamide-gel electrophoresis. Proc. Natl. Acad. Sci. USA 87, 5827–5831.
Lee, V. M.-Y., Balin, B. J., Otvos, L., and Trojanowski, J. Q. (1991) A68-a major subunit of paired helical filaments and derivatized forms of normal tau. Science 251,675–678.
Ledesma, M. D., Bonay, P., Colaco, C., and Avila, J. (1994) Analysis of microtu-bule-associated protein tau glycation in paired helical filaments. J. Biol. Chem. 269,21,614–21,619.
Yan, S.-D., Chen, X., Schmidt, A.-M., Brett, J., Godman, G., Zou, Y.-S., et al. (1994) Glycated tau protein in Alzheimer’s disease: a mechanism for induction of oxidant stress. Proc. Natl. Acad. Sci. USA 91, 7787–7791.
Smith, M. A., Sayre, L. M., Monnier, V. M., and Perry, G. (1995) Radical AGEing in Alzheimer disease. Trends Neurosci. 18, 172–176.
Smith, M. A., Siedlak, S. L., Richey, P. L., Nagaraj, R. H., Elhammer, A., and Perry, G. (1996) Quantitative solubilization and analysis of insoluble paired helical filaments from Alzheimer disease. Brain Res. 717, 99–108.
Selkoe, D. J., Abraham, C., and Ihara, Y. (1982a) Brain TGase: in vitro crosslinking of human neurofilament proteins into insoluble polymers. Proc. Natl. Acad. Sci. USA 79,6070–6074.
Selkoe, D. J., Ihara, Y., and Salazar, F. J. (1982b) Alzheimer’s disease: insolubility of partially purified paired helical filaments in sodium dodecyl sulfate and urea. Science 215,1243–1245.
Miller, M. L. and Johnson, G. W. (1995) Transglutaminase cross-linking of the x protein. J. Neurochem. 65, 1760–1770.
Appelt, D. M., Kopen, G. C., Boyne, L. J., and Balin, B. J. (1996a) Localization of transglutaminase in hippocampal neurons: implications for Alzheimer’s disease. J. Histochem. Cytochem. 44,1421–1427.
Appelt, D. M., Howard, M. P., Loewy, A. G., and Balin, B. J. (1996b) Insoluble NFTs from Alzheimer disease contain transglutaminase-catalyzed Glu-Lys bonds as revealed by their sensitivity to a novel isopeptidase. Soc. Neuroscience Abstr. 22, 559.9.
Appelt, D. M. and Balin, B. J. (1997) The association of tissue transglutaminase with human recombinant tau results in the formation of insoluble filamentous structures. Brain Res. 745, 21–31.
Johnson, G. V. W., Cox, T. C., Lockhart, J. P., Zinnerman, M. D., Miller, M. L., and Powers, R. E. (1997) Transglutaminase activity is increased in Alzheimer’s disease brain. Brain Res. 751, 323–329.
Hand, D., Perry, M. J. M., and Haynes, L. W. (1993) Cellular TGases in neural development. Int. J. Devel. Neurosci. 11,709–720.
Folk, J. E. and Finlayson, J. S. (1977) The ε-(gamma-glutamyl)lysine cross-link and the catalytic role of Tgases. Adv. Protein Chem. 31, 1–133.
Lorand, L. (1988) TGase-mediated cross-linking of proteins and cell aging: the erythrocyte and lens models. Adv. Exp. Med. Biol. 231, 79–94.
Fesus, L., Thomazy, V., and Falus, A. (1987) Induction and activation of tissue TGase during programmed cell death. FEBS Lett. 244, 104–108.
Gilad, G. M. and Kupmar, V. (1982) Absence of functional recovery after spinal hemisections in mice genetically deficient in hemolytic complement. Exp. Neurol. 767, 666–669.
Gilad, G. M. and Varon, L. E. (1985) TGase activity in rat brain: characterization, distribution and changes with age. J. Neurochem. 45,1522–1526.
Byrd, J. C. and Lichti, U. (1987) Two types of TGase in the PC12 pheochromocy-toma cell line. Stimulation by sodium butyrate. J. Biol. Chem. 262,11,699–11,705.
Miller, C. J. and Anderton, B. H. (1986) TGase and the neuronal cytoskeleton in Alzheimer’s disease. J. Neurochem. 46,1912–1922.
Dudek, S. M. and Johnson, G. V. W. (1993) TGase catalyzes the formation of sodium dodecylsulfate-insoluble, Alz 50-reactive polymers of tau. J. Neurochem. 61, 1159–1162.
Benzing, W. C., Ikonomovic, I. M., Brady, D. R., Mufson, E. J., and Armstrong, D. M. (1993) Evidence that transmitter-containing dystrophic neurites precede paired helical filaments and Alz-50 formation within senile plaques in the amygdala of nondemented elderly and patients with Alzheimers disease. J. Comp. Neurol. 224, 176–191.
Hyman, B. T., Van Hoesen, G. W., Wolozin, B. L., Davies, P., Kromer, J. L., and Damasio, A. R. (1988) Alz-50 antibody recognizes Alzheimer-related neuronal changes. Ann. Neurol. 23, 371–379.
Carmel, G., Mager, E. M., Binder, L. J., and Kuret, J. (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J. Biol. Chem. 271, 32789–32795.
Gache, Y., Guilleminot, J., Ricolfi, F., Theiss, G., and Nunez, J. (1992) A tau-related protein of 130 kDa is present in Alzheimer brain. J. Neurochem. 58, 2005–2010.
Barsigian, C, Stern, A. M., and Martinez, J. (1991) Tissue (type II) transglutaminase covalently incorporates itself, fibrinogen, or fibronectin into high molecular weight complexes on the extracellular surface of isolated hepatocytes. J. Biol. Chem. 266, 22,501–22,509.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2000 Humana Press Inc., Totowa, NJ
About this protocol
Cite this protocol
Balin, B.J., Appelt, D.M. (2000). Transglutaminase-Catalyzed Formation of Alzheimer-Like Insoluble Complexes from Recombinant Tau. In: Hooper, N.M. (eds) Alzheimer's Disease. Methods in Molecular Medicine™, vol 32. Humana Press. https://doi.org/10.1385/1-59259-195-7:395
Download citation
DOI: https://doi.org/10.1385/1-59259-195-7:395
Publisher Name: Humana Press
Print ISBN: 978-0-89603-737-3
Online ISBN: 978-1-59259-195-4
eBook Packages: Springer Protocols