QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (69) Citing Articles via Google Scholar Google Scholar Articles by Fath, T. Articles by Brandt, R. Search for Related Content PubMed PubMed Citation Articles by Fath, T. Articles by Brandt, R.

 Previous Article  |  Next Article 

The Journal of Neuroscience, November 15, 2002, 22(22):9733-9741

Tau-Mediated Cytotoxicity in a Pseudohyperphosphorylation Model of Alzheimer's Disease

Thomas Fath^{1, 2}, Jochen Eidenmüller², and Roland Brandt^{1, 2}

¹ Department of Neurobiology, University of Osnabrück, 49076 Osnabrück, Germany, and ² Interdisziplinäres Zentrum für Neurowissenschaften, Department of Neurobiology, University of Heidelberg, 69120 Heidelberg, Germany

Aggregation and increased phosphorylation of tau at selected sites ("hyperphosphorylation") are histopathological hallmarks of Alzheimer's disease (AD). However, it is not known whether the tau pathology has a primary role during neuronal degeneration. To determine the role of tau hyperphosphorylation in AD, pseudohyperphosphorylated tau (PHP-tau) that simulates disease-like permanent, high stoichiometric tau phosphorylation and mimics structural and functional aspects of hyperphosphorylated tau was expressed in neural cells. In differentiated PC12 cells, PHP-tau exhibited reduced microtubule interaction and failed to stabilize the microtubule network compared with exogenously expressed wild-type tau (wt-tau). During longer culture, PHP-tau exerted a cytotoxic effect, whereas wt-tau was neutral. PHP-tau-mediated cytotoxicity was associated with an induction of apoptotic cell death as characterized by chromatin condensation, DNA fragmentation, and caspase-3 activation in the absence of detectable protein aggregates. Furthermore, PHP-tau expression specifically sensitized the cells for other apoptotic stimuli (colchicine and staurosporine). Herpes simplex virus-mediated overexpression of PHP-tau induced degeneration associated with an induction of apoptotic mechanisms also in terminally differentiated human CNS model neurons. Partially pseudophosphorylated constructs caused an intermediate toxicity. The data provide evidence for a neurotoxic "gain of function" of soluble tau during AD as a result of structural changes that are induced by a cumulative, high stoichiometric tau phosphorylation. PHP-tau-expressing cells and organisms could provide a useful system to identify mechanisms that contribute to tau-mediated toxicity.

Key words: tau; Alzheimer's disease; phosphorylation; apoptosis; hyperphosphorylation; human model neurons

---

Copyright © 2002 Society for Neuroscience  0270-6474/02/22229733-09$05.00/0

This article has been cited by other articles:

				C. Tackenberg and R. Brandt Divergent Pathways Mediate Spine Alterations and Cell Death Induced by Amyloid-{beta}, Wild-Type Tau, and R406W Tau J. Neurosci., November 18, 2009; 29(46): 14439 - 14450. [Abstract] [Full Text] [PDF]

				F. Liu, J. Shi, H. Tanimukai, J. Gu, J. Gu, I. Grundke-Iqbal, K. Iqbal, and C.-X. Gong Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease Brain, July 1, 2009; 132(7): 1820 - 1832. [Abstract] [Full Text] [PDF]

				H.-L. Li, H.-H. Wang, S.-J. Liu, Y.-Q. Deng, Y.-J. Zhang, Q. Tian, X.-C. Wang, X.-Q. Chen, Y. Yang, J.-Y. Zhang, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration PNAS, February 27, 2007; 104(9): 3591 - 3596. [Abstract] [Full Text] [PDF]

				H. Ding, T. A. Matthews, and G. V. W. Johnson Site-specific Phosphorylation and Caspase Cleavage Differentially Impact Tau-Microtubule Interactions and Tau Aggregation J. Biol. Chem., July 14, 2006; 281(28): 19107 - 19114. [Abstract] [Full Text] [PDF]

				N. Shahani, S. Subramaniam, T. Wolf, C. Tackenberg, and R. Brandt Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices. J. Neurosci., May 31, 2006; 26(22): 6103 - 6114. [Abstract] [Full Text] [PDF]

				D. Cripps, S. N. Thomas, Y. Jeng, F. Yang, P. Davies, and A. J. Yang Alzheimer Disease-specific Conformation of Hyperphosphorylated Paired Helical Filament-Tau Is Polyubiquitinated through Lys-48, Lys-11, and Lys-6 Ubiquitin Conjugation J. Biol. Chem., April 21, 2006; 281(16): 10825 - 10838. [Abstract] [Full Text] [PDF]

				G. Amadoro, M. T. Ciotti, M. Costanzi, V. Cestari, P. Calissano, and N. Canu From the Cover: NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation PNAS, February 21, 2006; 103(8): 2892 - 2897. [Abstract] [Full Text] [PDF]

				M. Necula and J. Kuret Pseudophosphorylation and Glycation of Tau Protein Enhance but Do Not Trigger Fibrillization in Vitro J. Biol. Chem., November 26, 2004; 279(48): 49694 - 49703. [Abstract] [Full Text] [PDF]

				G. V. W. Johnson and W. H. Stoothoff Tau phosphorylation in neuronal cell function and dysfunction J. Cell Sci., November 15, 2004; 117(24): 5721 - 5729. [Abstract] [Full Text] [PDF]

				A. d. C. Alonso, A. Mederlyova, M. Novak, I. Grundke-Iqbal, and K. Iqbal Promotion of Hyperphosphorylation by Frontotemporal Dementia Tau Mutations J. Biol. Chem., August 13, 2004; 279(33): 34873 - 34881. [Abstract] [Full Text] [PDF]

				H. Shimura, Y. Miura-Shimura, and K. S. Kosik Binding of Tau to Heat Shock Protein 27 Leads to Decreased Concentration of Hyperphosphorylated Tau and Enhanced Cell Survival J. Biol. Chem., April 23, 2004; 279(17): 17957 - 17962. [Abstract] [Full Text] [PDF]

				J. AVILA, J. J. LUCAS, M. PEREZ, and F. HERNANDEZ Role of Tau Protein in Both Physiological and Pathological Conditions Physiol Rev, April 1, 2004; 84(2): 361 - 384. [Abstract] [Full Text] [PDF]

				P. K. Krishnamurthy and G. V. W. Johnson Mutant (R406W) Human Tau Is Hyperphosphorylated and Does Not Efficiently Bind Microtubules in a Neuronal Cortical Cell Model J. Biol. Chem., February 27, 2004; 279(9): 7893 - 7900. [Abstract] [Full Text] [PDF]

				H. Shimura, D. Schwartz, S. P. Gygi, and K. S. Kosik CHIP-Hsc70 Complex Ubiquitinates Phosphorylated Tau and Enhances Cell Survival J. Biol. Chem., February 6, 2004; 279(6): 4869 - 4876. [Abstract] [Full Text] [PDF]

				M. Cyr, J.-M. Beaulieu, A. Laakso, T. D. Sotnikova, W.-D. Yao, L. M. Bohn, R. R. Gainetdinov, and M. G. Caron Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons PNAS, September 16, 2003; 100(19): 11035 - 11040. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help