# Determining the Role of Retrotransposon LINE-1 in Alzheimers Disease

> **NIH NIH R61** · RHODE ISLAND HOSPITAL · 2020 · $402,500

## Abstract

Abstract of the proposed research
In response to the NIH NOT-AG-20-008, the current Alzheimer’s Disease study pilot project
administrative supplement application is to expand the parent R61 award entitled “Repressing
Retrotransposon LINE-1: New Concepts for Osteoarthritis Treatment”, which is not focused on
Alzheimer’s disease and its related dementias (ADRD), to allow it to develop a focus on ADRD.
As administrative supplements, the work proposed here is within the scope and a natural
extension of the research of the R61. The R61 focuses on discovering mechanisms of aging
and injury associated joint degenerative diseases and developing prevention and treatment
strategies for such degenerative diseases. During this process, we found common pathological
mechanisms shared by both skeletal and neural degenerative diseases during aging, in
particular between aging-associated osteoarthritis (OA) and ADRD. Recent evidence indicate
that de-repression of retrotransposon LINE-1 or L1, which accounts for 17 percent of human
genome, are involved in inflammation and degeneration of both cartilage joint and brain tissues
during aging. Thus, the methodologies we have developed to study the relationship between L1
and cartilage joint degeneration can be used to determine the cause-effect relationship between
L1 and ADRD. The innovative hypothesis is that, during aging-associated AD, the cellular
content of L1 is 1) significantly increased in the brain and 2) responsible for stimulation of
inflammation and A accumulation that lead to neurodegeneration. If so, AD pathogenesis can
be inhibited by repressing L1 using FDA-approved anti-viral drug nucleoside reverse
transcriptase inhibitors (NRTIs). This hypothesis will be tested through two aims. The first aim is
to characterize aging induced L1 de-repression in an AD transgenic mouse model. It will
establish whether early-onset of AD would result in de-repression of the L1 levels in mouse
brain. The second aim is to determine whether NRTIs inhibit AD pathogenesis by repressing L1
levels in AD animal models in vivo. NRTI nucleoside cytidine analogue Lamivudine will be
tested for its ability of inhibiting neurodegeneration in AD transgenic mice. It will establish the
efficacy and the window of intervention for NRTI to modify neurodegeneration in AD animal
models in vivo. If successful, NRTIs, which are readily available, may be re-purposed for AD
treatment in human. It will not only change the concepts that drive the AD research field, but
also impact the clinical practice of how we treat AD patients.

## Key facts

- **NIH application ID:** 10123582
- **Project number:** 3R61AR076807-02S1
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** QIAN CHEN
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 3
- **Project period:** 2019-09-16 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123582

## Citation

> US National Institutes of Health, RePORTER application 10123582, Determining the Role of Retrotransposon LINE-1 in Alzheimers Disease (3R61AR076807-02S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10123582. Licensed CC0.

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