Disruptions in transposable elements and gene networks occur before the onset of tauopathy in a humanized mouse model of AD

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is an age‐related neurodegenerative disorder culminating in dementia with additional non‐cognitive behavioral and metabolic symptomatology such as hyperactivity and altered sleep/wake patterns, which promote weight loss. In demented patients weight loss is associated with adverse outcomes, including accelerated AD progression and higher institutionalization. Mouse models of tau deposition, such as Tg4510 mice, also have negative energy balance. Tg4510 mice, which express a P301L mutant variant of human tau, develop both cognitive and non‐cognitive symptoms. To identify early pre‐symptomatic factors affecting AD, we analyzed RNA‐seq data from young, pre‐tauopathic Tg4510 mice to identify gene and transposable elements (TE) expression changes that may initiate the behavioral and metabolic derangements in AD.MethodsWe analyzed RNA‐seq from hippocampi of 2 month old Tg4510 mice (n=5) vs. controls (n=6). Using our established TTESA pipeline, reads were aligned to reference genome and measured gene expression or TEs with featureCounts. Pathway enrichment analysis using Visual Annotation Display was used to discover common functional themes using Gene Ontology and Mammalian Phenotype Ontology.ResultsTTESA results detected the majority of significantly differentially expressed TEs were retrotransposons (68%), which consisted mainly of long terminal repeats (LTRs; 70%) and some LINE retroelements (30%) in young transgenic mice. VLaD pathway analysis revealed several biological processes upregulated in transgenic mice, including defense, inflammation, and immune system processes and related categories of myeloid leukocyte activation and aggregation, cytokine production, T cell activation, B cell activation, regulation of natural killer cells, regulation of IL‐6 and TNF production, and TLR3 signaling. Likewise, genes invoked in the defense response to virus, were significantly increased. Notably, downregulation of genes associated with brain developmental processes, such as synaptic signaling, regulation of long‐term synaptic depression, chemical synaptic transmission, and neuronal structures, such as neuronal projections, proximal dendrites, and presynaptic membranes. Lastly, non‐cognitive behavioral pathways were downregulated, such as the regulation of circadian sleep/wake cycle.ConclusionsBased on our data, we conclude that early dysregulation of TEs may act as initial trigger altering neural gene expression networks underlying neuronal development, behavioral, cellular defense mechanisms and immune responses to viruses in this humanized mouse model of AD.