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

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.

journal_name

Alzheimers Res Ther

journal_title

Alzheimer's research & therapy

authors

Fromholt S,Reitano C,Brown H,Lewis J,Borchelt DR

doi

10.1186/s13195-016-0202-1

subject

Has Abstract

pub_date

2016-09-05 00:00:00

pages

36

issn

1758-9193

pii

10.1186/s13195-016-0202-1

journal_volume

8

pub_type

杂志文章

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