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

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 12, 2004, 24(19):4657-4667; doi:10.1523/JNEUROSCI.0797-04.2004

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 (44) Citing Articles via Google Scholar Google Scholar Articles by Zhang, B. Articles by Lee, V. M.-Y. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Lee, V. M.-Y.

 Previous Article  |  Next Article 

Neurobiology of Disease
Retarded Axonal Transport of R406W Mutant Tau in Transgenic Mice with a Neurodegenerative Tauopathy

Bin Zhang, Makoto Higuchi, Yasumasa Yoshiyama, Takeshi Ishihara, Mark S. Forman, Dan Martinez, Sonali Joyce, John Q. Trojanowski, and Virginia M.-Y. Lee

The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, and Institute on Aging, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Intracellular accumulations of filamentous tau inclusions are neuropathological hallmarks of neurodegenerative diseases known as tauopathies. The discovery of multiple pathogenic tau gene mutations in many kindreds with familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) unequivocally confirmed the central role of tau abnormalities in the etiology of neurodegenerative disorders. To examine the effects of tau gene mutations and the role of tau abnormalities in neurodegenerative tauopathies, transgenic (Tg) mice were engineered to express the longest human tau isoform (T40) with or without the R406W mutation (RW and hWT Tg mice, respectively) that is pathogenic for FTDP-17 in several kindreds. RW but not hWT tau Tg mice developed an age-dependent accumulation of insoluble filamentous tau aggregates in neuronal perikarya of the cerebral cortex, hippocampus, cerebellum, and spinal cord. Significantly, CNS axons in RW mice contained reduced levels of tau when compared with hWT mice, and this was linked to retarded axonal transport and increased accumulation of an insoluble pool of RW but not hWT tau. Furthermore, RW but not hWT mice demonstrated neurodegeneration and a reduced lifespan. These data indicate that the R406W mutation causes reduced binding of this mutant tau to microtubules, resulting in slower axonal transport. This altered tau function caused by the RW mutation leads to increased accumulation and reduced solubility of RW tau in an age-dependent manner, culminating in the formation of filamentous intraneuronal tau aggregates similar to that observed in tauopathy patients.

Key words: tau R406W mutation; transgenic mice; tauopathy; FTDP-17; axonal transport; tau proteins

---

Received Oct 22, 2003; revised March 31, 2004; accepted March 31, 2004.

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]

				K. Schindowski, A. Bretteville, K. Leroy, S. Begard, J.-P. Brion, M. Hamdane, and L. Buee Alzheimer's Disease-Like Tau Neuropathology Leads to Memory Deficits and Loss of Functional Synapses in a Novel Mutated Tau Transgenic Mouse without Any Motor Deficits Am. J. Pathol., August 1, 2006; 169(2): 599 - 616. [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]

				K. Boekhoorn, D. Terwel, B. Biemans, P. Borghgraef, O. Wiegert, G. J. A. Ramakers, K. de Vos, H. Krugers, T. Tomiyama, H. Mori, et al. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J. Neurosci., March 29, 2006; 26(13): 3514 - 3523. [Abstract] [Full Text] [PDF]

				M. A. Utton, W. J. Noble, J. E. Hill, B. H. Anderton, and D. P. Hanger Molecular motors implicated in the axonal transport of tau and {alpha}-synuclein J. Cell Sci., October 15, 2005; 118(20): 4645 - 4654. [Abstract] [Full Text] [PDF]

				M. Higuchi, B. Zhang, M. S. Forman, Y. Yoshiyama, J. Q. Trojanowski, and V. M.-Y. Lee Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies J. Neurosci., October 12, 2005; 25(41): 9434 - 9443. [Abstract] [Full Text] [PDF]

				R. A. Halverson, J. Lewis, S. Frausto, M. Hutton, and N. A. Muma Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice J. Neurosci., February 2, 2005; 25(5): 1226 - 1233. [Abstract] [Full Text] [PDF]

				B. Zhang, A. Maiti, S. Shively, F. Lakhani, G. McDonald-Jones, J. Bruce, E. B. Lee, S. X. Xie, S. Joyce, C. Li, et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model PNAS, January 4, 2005; 102(1): 227 - 231. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help