Generation of a new transgenic mouse model for assessment of tau gene silencing therapies.
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.
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
Susan
S
Fromholt
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.
Christian
C
Reitano
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA.|McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA.
Hilda
H
Brown
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA. jada.lewis@ufl.edu.|McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA. jada.lewis@ufl.edu.
Jada
J
Lewis
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL, USA. drb1@ufl.edu.|McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA. drb1@ufl.edu.
David R
DR
Borchelt
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D024801:Tauopathies / Q000628:therapy*; D013752:Tetracycline; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
C054369:MAPT protein, human; D012333:RNA, Messenger; D025801:Ubiquitin; D016875:tau Proteins; D008156:Luciferases; D013752:Tetracycline; D004318:Doxycycline
Alzheimer’s disease; Gene-silencing; Tau; Transgenic mouse model