Temporal and spatially controlled APP transgene expression using Cre-dependent alleles

Abstract

While 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 Cre and 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 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.

Need of orthogonal approaches in neurological disease modeling in mouse

“…Although tTA-dependent alleles corresponding to various proteinopathies already exist, one of the significant limitations of current mouse models for neurodegenerative diseases, is their failure to properly mimic the disorder's time course (Koller et al, 2022 ). For example, in Alzheimer's disease models, clinical signs often manifest earlier than in the corresponding human pathology, implying a need to delay the formation of the pathological amyloid plaques.…”

“…Additionally, the limited availability of CNS-targeting tTA driver lines poses a challenge for regional or cell-type-specific studies. To address these limitations, Koller and colleagues proposed using a Cre-to-tTA converter allele to yield Cre-dependent expression of an existing Tet-regulated transgene (Koller et al, 2022 ). This system allows to draw from the extensive repertoire of Cre driver lines for precise spatial control, including spatiotemporal control when considering Cre-ER T2 drivers.…”

Differential usage of DNA modifications in neurons, astrocytes, and microglia

“…This article is a US Government work. It is not subject to copyright under 17 USC 105 The copyright holder for this preprint (which this version posted June 7, 2023. ; https://doi.org/10.1101/2023.06.05.543497 doi: bioRxiv preprint field we combine the Nuclear Tagging and Translating Ribosome Affinity Purification (NuTRAP) mouse line [30][31][32] with a well-established neuronal-specific inducible cre-recombinase system (Camk2a-cre/ERT2 [33][34][35][36]) to perform a paired translatomic and epigenomic analysis of excitatory glutamatergic pyramidal neurons in the hippocampus [37][38][39][40]. To gain a broader perspective, we compare our neuronal findings to astrocytic and microglial data [41].…”

First person – Emily Koller

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Emily Koller is first author on ‘ Temporal and spatially controlled APP transgene expression using Cre-dependent alleles ’, published in DMM. Emily is a postdoctoral associate in the lab of Joanna Jankowsky, PhD at Baylor College of Medicine, Houston, TX, USA, investigating the impact of ageing in Alzheimer's disease, and is also interested in developing therapeutic interventions for diseases of the brain.…”