Inbred Mice Again at Stake: How the Cognitive Profile of the Wild-Type Mouse Background Discloses Pathogenic Effects of APP Mutations

Abstract

Increasing efforts have been made in the last decades to increase the face validity of Alzheimer's disease (AD) mouse models. Main advancements have consisted in generating AD mutations closer to those identified in humans, enhancing genetic diversity of wild-type backgrounds, and choosing protocols much apt to reveal AD-like cognitive dysfunctions. Nevertheless, two aspects remain less considered: the cognitive specialization of inbred strains used as recipient backgrounds of mutations and the heuristic importance of studying destabilization of memory circuits in pre-symptomatic mice facing cognitive challenges. This article underscores the relevance of these behavioral/experimental aspects by reviewing data which show that (i) inbred mice differ in their innate predisposition to rely on episodic vs. procedural memory, which implicates differential sensitivity to mutations aimed at disrupting temporal lobe-dependent memory, and that (ii) investigating training-driven neural alterations in asymptomatic mutants unveils early synaptic damage, which considerably anticipates detection of AD first signs.

Genetic background influences the 5XFAD Alzheimer's disease mouse model brain proteome

“…Genetically diverse, wild-derived transgenic mice produced strong differentiation of phenotypes associated with important human disease features, including cognitive-like changes, neurodegeneration, and amyloid dynamics. However, this method of introducing genetic diversity has been cautioned due to the lack of rigorous characterization in the absence of AD transgenes (Ammassari-Teule, 2022 ). The use of fully inbred parental lines, such as B6 and D2, which have been extensively characterized, overcomes this ambiguity.…”

“…Mouse models of AD have been almost exclusively developed on a single inbred strain, the C57BL/6J (B6). The selection of B6 as the ideal background for developing AD model systems has been largely due to their desirable behavioral characteristics and the development of cognitive impairment and amyloid deposition (Lassalle et al, 2008 ; Sultana et al, 2019 ; Forner et al, 2021 ; Ammassari-Teule, 2022 ). For instance, the commonly used 5XFAD transgenic model was developed on the B6 background to overcome variable phenotypes produced on a hybrid background (Oblak et al, 2021 ).…”

Genetic background influences the 5XFAD Alzheimer’s disease mouse model brain proteome

“…Mouse models of AD have been almost exclusively developed on a single inbred strain, the C57BL/6J (B6). The selection of B6 as the ideal background for developing AD model systems has been largely due to their desirable behavioral characteristics and the development of cognitive impairment and amyloid deposition (Lassalle et al, 2008;Sultana et al, 2019;Forner et al, 2021;Ammassari-Teule, 2022). For instance, the commonly used 5XFAD transgenic model was developed on the B6 background to overcome variable phenotypes produced on a hybrid background (Oblak et al, 2021).…”