Generation of a new transgenic mouse model for assessment of tau gene silencing therapies

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.