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

> **NIH NIH R56** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $1,012,723

## Abstract

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. Com...

## Key facts

- **NIH application ID:** 10670482
- **Project number:** 1R56AG078970-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** DOUGLAS F NIXON
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,012,723
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-06-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670482

## Citation

> US National Institutes of Health, RePORTER application 10670482, The Role of Transposable Elements in Healthy Aging and in Alzheimer's Disease (1R56AG078970-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10670482. Licensed CC0.

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