Identifying human‐relevant genetic interactors of APOE using genetically diverse mouse strains

Abstract

AbstractBackgroundAPOEe4 is the greatest risk factor for late‐onset Alzheimer’s disease (AD), accounting for ∼30% of genetic risk and significantly decreasing age of onset. APOE is implicated to play central roles across multiple pathways such as neuroinflammation, lipid metabolism and vascular health. Current mechanistic work has introduced humanized APOE alleles in mouse models of AD on a single laboratory mouse strain, C57BL/6J (B6). Recent work from our lab has taken advantage of genetically diverse wild‐derived strains which were captured from different geographical regions and then inbred, thus, their genomes are closer to recapitulating combinations that would exist in the natural world. Here, we seek to identify and validate human‐relevant genetic interactors of APOE within these contexts and in the presence of amyloid.MethodNovel wild‐derived mice were developed by backcrossing the respective strain (PWK/PhJ, WSB/EiJ) to B6.APOEe4 (N5). These were crossed with congenic APP/PS1 carriers, and offspring intercrossed to generate cohorts of 4‐ and 8‐month males and females homozygous for APOEe4, with and without APP/PS1. A cohort of B6.APOEe4 carrying APP/PS1 were also generated for comparison. Neuropathology was assessed along with blood chemistry, and transcriptional profiling was performed on brain hemispheres.ResultBrain transcriptional profiling revealed that APOEe4 had the greatest impact on differential gene expression (dE) in the PWK genetic context at both timepoints, with the strongest effect in females. Comparison with AMP‐AD human‐derived consensus clusters also indicated the broadest overlap when variants were present in the PWK context. Furthermore, APOEe4 genotype was sufficient to cause neuronal damage at 8 months, despite other studies indicating neuronal resilience to amyloid and aging in PWK. In both WSB and B6 carrying APP/PS1, APOEe4 increased the incidence and severity of cerebral amyloid angiopathy (CAA). Further neuropathological assessments are ongoing, and will be correlated with dE.ConclusionThis work highlights the importance of assessing risk alleles for AD in a variety of genetic contexts. We have also created genetically diverse panels of mice that carry humanized amyloid beta and humanized tau in that hope that these strains will provide an improved preclinical platform for therapeutic discovery and testing.