Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration

Stephanie J. Adams, Richard J.P. Crook, Michael DeTure, Suzanne J. Randle, Amy E. Innes, Xin Z. Yu, Wen Lang Lin, Brittany Dugger, Melinda McBride, Mike Hutton, Dennis W. Dickson, Eileen McGowan

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer's disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies.

Original languageEnglish (US)
Pages (from-to)1598-1609
Number of pages12
JournalAmerican Journal of Pathology
Volume175
Issue number4
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Adams, S. J., Crook, R. J. P., DeTure, M., Randle, S. J., Innes, A. E., Yu, X. Z., Lin, W. L., Dugger, B., McBride, M., Hutton, M., Dickson, D. W., & McGowan, E. (2009). Overexpression of wild-type murine tau results in progressive tauopathy and neurodegeneration. American Journal of Pathology, 175(4), 1598-1609. https://doi.org/10.2353/ajpath.2009.090462