Generation of a new transgenic mouse model for assessment of tau gene silencing therapies. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Fromholt, Susan; Reitano, Christian; Brown, Hilda; Lewis, Jada; Borchelt, David
• Is Part Of: Alzheimer's research & therapy. Volume 8:Issue 1(2016)
• Page Start: 1
• Page End: 7
• Publication Date: 2016-12
• Subjects: Alzheimer's disease -- Tau -- Gene-silencing -- Transgenic mouse model; Alzheimer's disease -- Periodicals; 616.831005
• DOI: 10.1186/s13195-016-0202-1
• Languages: English
• ISSNs: 1758-9193

Abstract

Abstract Background Targeting the expression of genes has emerged as a potentially viable therapeutic approach to human disease. In Alzheimer's disease, therapies that silence the expression of tau could be a viable strategy to slow disease progression. Methods We produced a novel strain of transgenic mice that could be used to assess the efficacy of gene knockdown therapies for human tau, in live mice. We designed a tetracycline-regulated transgene construct in which the cDNA for human tau was fused to ubiquitin and to luciferase to create a single fusion polyprotein, termed TUL. Results When expressed in brain, the TUL polyprotein was cleaved by ubiquitin-processing enzymes to release the luciferase as an independent protein, separating the half-life of luciferase from the long-lived tau protein. Treatment of bigenic tTA/TUL mice with doxycycline produced rapid declines in luciferase levels visualized by in vivo imaging and ex vivo enzyme measurement. Conclusions This new mouse model can be used as a discovery tool in optimizing gene targeting therapeutics directed to reduce human tau mRNA levels.