tetracycline and Tauopathies

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.. 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.. 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.. This new mouse model can be used as a discovery tool in optimizing gene targeting therapeutics directed to reduce human tau mRNA levels.

Topics: Animals; Brain; Disease Models, Animal; Doxycycline; Gene Silencing; Genetic Therapy; Humans; Luciferases; Mice, Transgenic; RNA, Messenger; tau Proteins; Tauopathies; Tetracycline; Ubiquitin