Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy

Chad Dickey, Clara Kraft, Umesh Jinwal, John Koren, Amelia Johnson, Laura Anderson, Lori Lebson, Daniel Lee, Dennis Dickson, Rohan De Silva, Lester I. Binder, David Morgan, Jada Lewis

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points, suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust, pre-tangle-like accumulation of phospho-tau in 1-month-old mice, this material was cleared by 3 months, indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult. We also found that while heat shock protein expression increased with normal aging, this process was accelerated in rTg4510 mice. Moreover, by exploiting an exon 10 (-) specific antibody, we demonstrated that endogenous mouse tau turnover was slowed in response to human tau over-expression, and that this endogenous tau adopted disease-related properties. These data suggest that a younger brain fails to develop lasting tau pathology despite elevated levels of phosphorylated tau, perhaps because of reduced expression of stress-related proteins. Moreover, we show that the active production of small amounts of abnormal tau protein facilitates dysfunction and accumulation of otherwise normal tau, a significant implication for the pathogenesis of patients with Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)228-238
Number of pages11
JournalAmerican Journal of Pathology
Volume174
Issue number1
DOIs
StatePublished - Jan 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Dickey, C., Kraft, C., Jinwal, U., Koren, J., Johnson, A., Anderson, L., Lebson, L., Lee, D., Dickson, D., De Silva, R., Binder, L. I., Morgan, D., & Lewis, J. (2009). Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy. American Journal of Pathology, 174(1), 228-238. https://doi.org/10.2353/ajpath.2009.080764