Disentangling the determinants of transposable element expression in cognitive aging and Alzheimer's disease deficits using the AD‐BXD mouse population.

Background: Alzheimer's Disease (AD) is a complex multifaceted disease that is mediated by multiple unidentified genetic and environmental factors. One such factor that has been implicated, but is yet to be fully understood, is the role of transposable elements (TE) in AD. Here, we explore the role and scope of TEs using genetically diverse population of mice carrying familial AD mutations (AD‐BXDs) and their non‐transgenic littermates (Ntg‐BXDs). Method: We quantified the expression levels of all known transposable elements (TEs) in the hippocampus using TEtranscripts (v.0.36) in 28 different mouse strains carrying familial AD mutations (AD‐BXDs) and in their non‐transgenic littermates (Ntg‐BXDs) at 6 and 14 months of age. Differentially abundant TEs as a function of genotype (Ntg vs 5XFAD) and age (6m vs 14m) were assessed using DESeq2. We assessed heritability of TE expression for TEs that were identified as significantly differential expressed from the above comparisons, to obtain an estimate of heritable variation in a genetically diverse population. Lastly, we correlated TE expression to short‐term and long‐term memory using contextual fear conditioning. Result: Differential expression analysis revealed higher number of differentially expressed TEs in the 14‐month age group between AD‐BxD and their Ntg littermate controls as compared to the 6‐month age group. Majority of these differentially expressed TE are upregulated and belong to the category of LTR transposons. Importantly, we observe high average heritable variation (h26m‐Ntg=0.65, h26m‐5xFAD=0.58, h214m‐Ntg =0.44, h214m‐5xFAD=0.79) across our genetically diverse AD‐BXD panel. Lastly, we find significant negative correlations among contextual fear conditioning phenotypes and TE expression in the 5XFAD genotype group in both our 6m and 14m age groups. Conclusion: Our findings reveal a role of transposable elements, particularly LTR transposons across our genetically diverse population of mice, specifically in our 14m 5xFAD cohort. This finding is in line with previously published studies of the prevalence of LTR transposons in tauopathy models but is the first to assess the abundance and report on the extent of heritable variation of TE along with their correlation to cognitive behavior in a genetically diverse but translationally relevant mouse population of human AD. [ABSTRACT FROM AUTHOR]