# Regulation and function of dsRNAs derived from retrotransposable elements in AD

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $636,922

## Abstract

Project Summary
The goal of this project is to better understand the regulation and function of RNA derived from
retrotransposable elements (RTEs) in Alzheimer’s disease (AD), with a focus on
double-stranded RNAs (dsRNAs). RTEs occupy roughly 40% of the human genome. They
constitute a major subgroup of transposons, defined as genomic sequences that mobilize using
a ‘copy-and-paste’ mechanism where an RNA intermediate is involved. To date, most RTEs
have lost the ability to mobilize to new locations, at least in normal physiological conditions.
However, these elements may still retain regulatory activities through expression of RTE-derived
RNAs. This functional aspect is particularly relevant in the human brain, where RTE expression
is highest compared to other tissues. Given the multi-copy nature of each family of RTEs, their
transcripts often form dsRNA structures, resulted from repetitive sequence content, bi-directional
transcription or natural sense-antisense transcript pairs. Numerous studies have shown that
aberrant expression of cellular dsRNAs is related to the pathogenesis of various human
diseases. Recently, increasing evidence supports the existence of enhanced RNA expression
from RTEs in neurodegenerative diseases, including AD. This expression leads to accumulation
of dsRNAs in neurons, which is correlated with, for example, loss of nuclear TDP-43 or burden of
tau tangles. As a result of dsRNA accumulation, type I IFN response may be elicited in neurons,
which may contribute to AD pathogenesis. In this project, we aim to determine the identity and
origin of AD-relevant dsRNAs derived from RTEs and experimentally validate their functional
relevance in neurons. In addition, we will examine the impact of RNA-binding proteins (including
ADAR1) on RTE-derived dsRNAs and their functional relevance to AD. This work will allow a
previously unattained level of understanding of the regulation and function of RTE-derived
dsRNAs in AD and provide new insights to better understand RTE-related disease mechanisms.

## Key facts

- **NIH application ID:** 10690083
- **Project number:** 5R01AG078950-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Xinshu Grace Xiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $636,922
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690083

## Citation

> US National Institutes of Health, RePORTER application 10690083, Regulation and function of dsRNAs derived from retrotransposable elements in AD (5R01AG078950-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690083. Licensed CC0.

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