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Updated: Sep 27, 2025
In vivo Application of the REMOTE-control System for the Manipulation of Endogenous Gene Expression
Published on: March 29, 2019
Temporal and spatially controlled APP transgene expression using Cre-dependent alleles
Emily J Koller1, Melissa Comstock1, Jonathan C Bean1
1Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Although a large number of mouse models have been made to study Alzheimer's disease, only a handful allow experimental control over the location or timing of the protein being used to drive pathology. Other fields have used the Cre and the tamoxifen-inducible CreER driver lines to achieve precise spatial and temporal control over gene deletion and transgene expression, yet these tools have not been widely used in studies of neurodegeneration. Here, we describe two strategies for harnessing the wide range of Cre and CreER driver lines to control expression of disease-associated amyloid precursor protein (APP) in modeling Alzheimer's amyloid pathology. We show that CreER-based spatial and temporal control over APP expression can be achieved with existing lines by combining a Cre driver with a tetracycline-transactivator (tTA)-dependent APP responder using a Cre-to-tTA converter line. We then describe a new mouse line that places APP expression under direct control of Cre recombinase using an intervening lox-stop-lox cassette. Mating this allele with a CreER driver allows both spatial and temporal control over APP expression, and with it, amyloid onset. This article has an associated First Person interview with the first author of the paper.
Insights
Researchers developed new mouse models for Alzheimer's disease (AD) research. These models offer precise control over the timing and location of amyloid precursor protein (APP) expression, advancing AD pathology studies.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Alzheimer's disease (AD) research heavily relies on mouse models.
- Existing models often lack precise control over the spatial and temporal expression of disease-driving proteins like amyloid precursor protein (APP).
- Cre and CreER driver lines offer spatial and temporal gene control but are underutilized in neurodegeneration studies.
Purpose of the Study:
- To present novel strategies for controlling APP expression in mouse models of Alzheimer's disease.
- To leverage Cre and CreER driver lines for precise spatial and temporal control of AD pathology.
- To facilitate more accurate modeling of amyloid pathology in Alzheimer's disease.
Main Methods:
- Developed two distinct strategies to control APP expression using Cre/CreER systems.
- Strategy 1: Combined a Cre driver with a tetracycline-transactivator (tTA)-dependent APP responder via a Cre-to-tTA converter line for CreER-based control.
- Strategy 2: Created a new mouse line with APP expression controlled by Cre recombinase through a lox-stop-lox cassette.
Main Results:
- Demonstrated successful spatial and temporal control over APP expression using the CreER system and the converter line.
- Showcased a new mouse line enabling direct Cre-mediated control of APP expression.
- Established that mating the new allele with a CreER driver allows precise control over APP expression and subsequent amyloid onset.
Conclusions:
- The developed strategies enable precise spatial and temporal control of APP expression in mouse models.
- These tools enhance the ability to study Alzheimer's disease amyloid pathology with greater experimental accuracy.
- The new mouse models offer significant advantages for investigating the mechanisms and potential treatments for Alzheimer's disease.
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