Altered transposable elements expression and gene networks remodeling precede disruptions in sleep/wake cycles in a tauopathy mouse model of AD

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is an widespread neurodegenerative disorder, common in elder and Veterans communities, culminating in dementia with non‐cognitive behavioral and metabolic symptoms, such as hyperactivity and altered sleep/wake patterns. In demented patients, sleep/wake cycle disruptions facilitate weight loss, which is associated with adverse outcomes like accelerated AD progression and higher institutionalization. Tg4510 mice, which express a P301L mutant variant of human tau, develop both cognitive and non‐cognitive symptoms. Several mouse models of tau deposition, including Tg4510 mice, also have negative energy balance. To identify early factors affecting AD, we measured locomotor, sleep/wake patterns in vivo, and analyzed RNA‐seq data from Tg4510 mice to identify gene and transposable elements (TE) expression changes involved in behavioral derangements in AD.MethodLocomotor activity, sleep and wake intervals and patterns were measured using in vivo metabolic cages for two weeks over 24 hr and day and night cycles from Tg4510 mice (n = 5‐7) vs. controls (n = 7‐10) before and after the onset of tauopathy (at 2 and 7 months of age respectively). In additional experiments, we analyzed RNA‐seq from hippocampi of Tg4510 mice (n = 5) vs. controls (n = 6). Using our established TTESA bioinformatics pipeline, reads were aligned to reference genome and expression of genes or TEs was measured with featureCounts. Pathway enrichment analysis using Visual Annotation Display was used to discover common functional and disease pathways using Gene Ontology, Protein Ontology, and Mammalian Phenotype Ontology.ResultWe observed altered locomotor and sleep patterns during the night phase starting in young Tg4510 vs. controls. TTESA results detected the majority of significantly differentially expressed TEs were retrotransposons (70%), which consisted mainly of long terminal repeats (LTRs; 70%) and some LINE retroelements (30%) and SINEs (<8%) in transgenic mice. VLaD pathway analysis revealed several biological processes upregulated in transgenic mice, including non‐cognitive behavioral pathways were downregulated, such as the regulation of circadian sleep/wake cycle with changes in the expression levels of Per2, Per3 (p<0.0001).ConclusionEarly dysregulation of TEs may be involved in rewiring gene expression networks underlying behavioral changes in wake and sleep cycles and other circadian patterns of behavior in this humanized mouse model of AD.