# Role of age-dependent repetitive element transcript dysregulation in Alzheimers disease

> **NIH NIH R03** · COLORADO STATE UNIVERSITY · 2022 · $152,000

## Abstract

Aging increases the risk for Alzheimer’s disease (AD), but the underlying mechanisms are poorly
understood. Next-generation sequencing studies (e.g., transcriptomics, RNA-seq) hold promise for identifying
novel mediators of brain aging/AD, but many have focused on coding genes only. Therefore, in response to
PAS-19-392, which emphasizes the “elucidation of genetic and epigenetic factors, genome stability, damage,
and DNA repair” in AD, in this R03 project we will explore an emerging topic in genome biology that may
provide insight into novel mechanisms of brain aging/AD. Specifically, we will determine if an age-related
accumulation of non-coding repetitive element (RE) transcripts is an important link between brain aging and
AD, and we will test related therapeutic strategies. Our rationale is that RE transcripts are predisposed to form
double-stranded RNA (dsRNA) that may stimulate neuroinflammation (a major and potentially targetable
mechanism of AD).
RE transcripts are derived from non-coding repetitive sequences that make up >60% of the human genome.
They are often ignored in transcriptome studies as “inactive”. However, growing evidence demonstrates that
dysregulation/activation of RE contributes directly to aging, and that certain pharmacological interventions may
prevent their effects. Some evidence also indicates that select RE transcripts are increased in AD, but our
preliminary data show that: a) global RE transcript levels (i.e., not just select RE) increase progressively with
age in human peripheral tissues, brains and neurons, and are associated with greater dsRNA; b) similar RE
transcripts and dsRNA are increased in AD patient brains and neurons; and c) RE transcript suppression may
inhibit neuro-inflammatory signaling. These observations suggest that an age-related, global dysregulation of
RE transcripts could play a central role in brain aging and age-related AD, perhaps by causing dsRNA-driven
neuroinflammation. We will investigate this possibility by: 1) conducting a large-scale bioinformatics analysis
of multiple RNA-seq datasets to identify key RE transcripts and RE-derived dsRNAs associated with brain
aging/AD and neuroinflammation; and 2) using neurons derived from human donors to test the efficacy of
clinically translatable, phytochemical compounds that reduce RE/dsRNA accumulation for inhibiting age/AD-
related neuroinflammation, and to identify the RE-derived dsRNAs that may cause neuroinflammation and AD
by stimulating the cellular dsRNA sensor protein kinase R (PKR, which has been linked with AD pathology).
These studies will provide a framework for a future R01 investigating the specific mechanisms by which age-
related RE transcript increases contribute to brain aging/AD and the potential for RE-targeting therapies to
treat or prevent brain aging/AD in vivo.

## Key facts

- **NIH application ID:** 10468222
- **Project number:** 5R03AG070562-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Thomas LaRocca
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $152,000
- **Award type:** 5
- **Project period:** 2021-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468222

## Citation

> US National Institutes of Health, RePORTER application 10468222, Role of age-dependent repetitive element transcript dysregulation in Alzheimers disease (5R03AG070562-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10468222. Licensed CC0.

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