The Role of Transposable Elements in Healthy Aging and in Alzheimer's Disease

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PROJECT ABSTRACT/SUMMARY Transposable Elements (TEs) comprise roughly 25% of human DNA and represent the largest class of biochemically functional DNA elements in mammalian genomes. Around 8% of the TEs in the human genome are human endogenous retroviruses (HERVs). A HERV consists of a set of genes (Gag, Pol, Env) that facilitate retrotransposition, and two promoter-containing identical long terminal repeats (LTRs) that flank these genes; a complete HERV typically spans several kilobases. Most HERVs are fragments or solitary LTRs. Since their identification numerous studies have looked for causative roles for HERVs in disease processes with findings that suggest a causative role in some cancers, autoimmune disorders and neurological disorders, and it is thought that dysregulation of HERVs plays a critical role in the pathophysiology of neurodegeneration and aging. In preliminary data, we have used our bioinformatic pipeline Telescope to identify differentially regulated HERVs in bulk RNAseq data and found district patterns of HERV expression across brain regions and neuronal cell types in AD and aging. In a tauopathy mouse model, we also found that the hyperactive Cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) signaling (cGAS) pathway contributes to tau toxicity since genetic reduction of cGAS protected against tau-mediated spatial learning and memory deficits in a tauopathy mouse model of AD. This led us to the hypothesis that HERVs are a source of viral nucleic acid that stimulate cGAS-STING leading to neuroinflammation, contributing to the etiology of AD. In three specific aims, we will first characterize and validate HERV expression from cell and brain samples from across the lifespan, and from age and sex matched patients with AD. Using our new bioinformatics pipeline, Stellarscope, we will determine differential expression of HERVs from single-nuclei RNA-sequencing data with loci-specific precision. Second, we will determine neuronal-associated gene- and HERV-expression pathways modulated by aging and AD, using participant-derived cell models of directly induced neurons (iNs). Unlike the immature neuronal populations generated from induced pluripotent stem cells, iNs retain neuron-specific, aging-associated gene- expression characteristics of the donor. We will determine if differences in HERV expression are reflective of accelerated age- and/or additional AD-associated transcriptional signatures are evident through the retrotranscriptional phenotyping of iNs derived from age-matched young cohorts and age-matched elder cohorts. Finally, we will ascertain how TEs can cause Tauopathy in a mouse model of AD. We will determine any beneficial effects of a cGAS inhibitor on TE expression before or after the onset of cognitive deficit in tauopathy mice and whether cGAS deletion changes TE expression. We will assess whether suppression of TEs will protect against tauopathy, and how inhibitors of cGAS change TE expression. Completion of the proposed study will identify novel mechanisms of TE expression in aging and in AD, and provide new therapeutic directions for pharmacological intervention.