Effect of mouse strain as a background for Alzheimer’s disease models on the clearance of amyloid-β

Abstract

Novel animal models of Alzheimer’s disease (AD) are relentlessly being developed and existing ones are being fine-tuned; however, these models face multiple challenges associated with the complexity of the disease where most of these models do not reproduce the full phenotypical disease spectrum. Moreover, different AD models express different phenotypes that could affect their validity to recapitulate disease pathogenesis and/or response to a drug. One of the most important and understudied differences between AD models is differences in the phenotypic characteristics of the background species. Here, we used the brain clearance index (BCI) method to investigate the effect of strain differences on the clearance of amyloid β (Aβ) from the brains of four mouse strains. These mouse strains, namely C57BL/6, FVB/N, BALB/c and SJL/J, are widely used as a background for the development of AD mouse models. Findings showed that while Aβ clearance across the blood-brain barrier (BBB) was comparable between the 4 strains, levels of LRP1, an Aβ clearance protein, was significantly lower in SJL/J mice compared to other mouse strains. Furthermore, these mouse strains showed a significantly different response to rifampicin treatment with regard to Aβ clearance and effect on brain level of its clearance-related proteins. Our results provide for the first time an evidence for strain differences that could affect ability of AD mouse models to recapitulate response to a drug, and opens a new research avenue that requires further investigation to successfully develop mouse models that could simulate clinically important phenotypic characteristics of AD.

MouseBytes, an open-access high-throughput pipeline and database for rodent touchscreen-based cognitive assessment

“…In addition to testing 3xTG-AD mice, we also tested APP/PS1 and the widely used 5xFAD mouse line. We chose to use the 5xFAD mice in a mixed genetic background (C57Bl6 and Swiss Jim Lambert -SJL), as this was the original background in which this mouse line was generated (Oakley et al, 2006), and it is the most commonly used background across several laboratories (Qosa and Kaddoumi, 2016). However, the SJL genetic background presents the Pdeb rd1 mutation that can lead to retinal degeneration (Clapcote et al, 2005) (see Materials and methods), which causes severe visual impairment in homozygosis.…”

Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia

“…We reasoned that one contributing factor, aside from the evolutionary distance between mouse and humans 7 , is that common laboratory mouse strains are highly inbred. Although genetic background profoundly impacts the biochemical and behavioral repertoires of mouse models of AD 8,9 , virtually all studies of neurodegeneration in mice rely on a single inbred strain 10,11 .…”

Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease

“…Here, the Nhlrc2 FINCA/− mice showed normal growth compared to their wild-type litter mates and did not develop a severe disease phenotype as described in FINCA patients. Environmental factors such as pathogens or the specific genetic background may play an additional role in triggering a more severe outcome of the disease in mice (Doetschman 2009 ; Keane et al 2011 ; Qosa and Kaddoumi 2016 ). Interestingly, NHLRC2 has recently been connected to immunological responses via initiation of phagocytosis in human macrophages, possibly through its effect on RhoA/Rac1 signalling, which controls actin polymerization and filopodia formation (Haney et al 2018 ; Yeung et al 2019 ).…”