This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal 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 Google Scholar Google Scholar Articles by Spires, T. L. Articles by Hyman, B. T. Search for Related Content PubMed PubMed Citation Articles by Spires, T. L. Articles by Hyman, B. T.

(American Journal of Pathology. 2006;168:1598-1607.)
© 2006 American Society for Investigative Pathology

Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Tara L. Spires^*, Jennifer D. Orne^*, Karen SantaCruz, Rose Pitstick, George A. Carlson, Karen H. Ashe^¶ and Bradley T. Hyman^*

From the Department of Neurology,^* MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts; the Department of Lab Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota; the McLaughlin Research Institute, Great Falls, Montana; the Departments of Neurology and Neuroscience, University of Minnesota Medical School, Minneapolis, Minnesota; and Geriatric Research, Education and Clinical Center,^¶ Minneapolis VA Hospital, Minneapolis, Minnesota

Correspondence: Address correspondence to Tara L. Spires, MassGeneral Institute for Neurodegenerative Disease, Alzheimer Unit, 114 16^th Street, Charlestown, MA 02129. E-mail: tspires{at}partners.org

Neurofibrillary tangles form in a specific spatial and temporal pattern in Alzheimer’s disease. Although tangle formation correlates with dementia and neuronal loss, it remains unknown whether neurofibrillary pathology causes cell death. Recently, a mouse model of tauopathy was developed that reversibly expresses human tau with the dementia-associated P301L mutation. This model (rTg4510) exhibits progressive behavioral deficits that are ameliorated with transgene suppression. Using quantitative analysis of PHF1 immunostaining and neuronal counts, we estimated neuron number and accumulation of neurofibrillary pathology in five brain regions. Accumulation of PHF1-positive tau in neurons appeared between 2.5 and 7 months of age in a region-specific manner and increased with age. Neuron loss was dramatic and region-specific in these mice, reaching over 80% loss in hippocampal area CA1 and dentate gyrus by 8.5 months. We observed regional dissociation of neuronal loss and accumulation of neurofibrillary pathology, because there was loss of neurons before neurofibrillary lesions appeared in the dentate gyrus and, conversely, neurofibrillary pathology appeared without major cell loss in the striatum. Finally, suppressing the transgene prevented further neuronal loss without removing or preventing additional accumulation of neurofibrillary pathology. Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death.

This article has been cited by other articles:

				C. Dickey, C. Kraft, U. Jinwal, J. Koren, A. Johnson, L. Anderson, L. Lebson, D. Lee, D. Dickson, R. de Silva, et al. Aging Analysis Reveals Slowed Tau Turnover and Enhanced Stress Response in a Mouse Model of Tauopathy Am. J. Pathol., January 1, 2009; 174(1): 228 - 238. [Abstract] [Full Text] [PDF]

				A. C. LeBoeuf, S. F. Levy, M. Gaylord, A. Bhattacharya, A. K. Singh, M. A. Jordan, L. Wilson, and S. C. Feinstein FTDP-17 Mutations in Tau Alter the Regulation of Microtubule Dynamics: AN "ALTERNATIVE CORE" MODEL FOR NORMAL AND PATHOLOGICAL TAU ACTION J. Biol. Chem., December 26, 2008; 283(52): 36406 - 36415. [Abstract] [Full Text] [PDF]

				J. B. Paulson, M. Ramsden, C. Forster, M. A. Sherman, E. McGowan, and K. H. Ashe Amyloid Plaque and Neurofibrillary Tangle Pathology in a Regulatable Mouse Model of Alzheimer's Disease Am. J. Pathol., September 1, 2008; 173(3): 762 - 772. [Abstract] [Full Text] [PDF]

				T. L. Spires-Jones, A. de Calignon, T. Matsui, C. Zehr, R. Pitstick, H.-Y. Wu, J. D. Osetek, P. B. Jones, B. J. Bacskai, M. B. Feany, et al. In Vivo Imaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons J. Neurosci., January 23, 2008; 28(4): 862 - 867. [Abstract] [Full Text] [PDF]

				S.-R. Ryoo, H. K. Jeong, C. Radnaabazar, J.-J. Yoo, H.-J. Cho, H.-W. Lee, I.-S. Kim, Y.-H. Cheon, Y. S. Ahn, S.-H. Chung, et al. DYRK1A-mediated Hyperphosphorylation of Tau: A FUNCTIONAL LINK BETWEEN DOWN SYNDROME AND ALZHEIMER DISEASE J. Biol. Chem., November 30, 2007; 282(48): 34850 - 34857. [Abstract] [Full Text] [PDF]

				K. Leroy, A. Bretteville, K. Schindowski, E. Gilissen, M. Authelet, R. De Decker, Z. Yilmaz, L. Buee, and J.-P. Brion Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice Am. J. Pathol., September 1, 2007; 171(3): 976 - 992. [Abstract] [Full Text] [PDF]

				A. A. Asuni, A. Boutajangout, D. Quartermain, and E. M. Sigurdsson Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements J. Neurosci., August 22, 2007; 27(34): 9115 - 9129. [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]