# Single-Cell Transposon Activation in the CNS during AD Progression: Sex-dependent Mechanisms

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2024 · $410,000

## Abstract

Abstract of the proposed research
In response to the NIH NOT-AG-23-032, the current Alzheimer’s Disease study pilot project
administrative supplement application is to expand the parent R01 award (1R01AG080141-01)
entitled “Cell Senescence Regulating Osteoarthritis Progression: Sex-dependent Mechanisms”
and help develop Alzheimer’s disease (AD) focused grants. The R01 focuses on discovering
mechanisms of aging-associated joint degenerative diseases. During this process, we found
common pathological mechanisms shared by both skeletal and neural degenerative diseases
during aging, specifically between aging-associated osteoarthritis (OA) and AD. Both OA and AD
present sexual dimorphism with higher prevalence in older females than older male. However,
the molecular mechanisms responsible for sexual dimorphisms of aging-associated degenerative
diseases are not clear. Recent evidence indicates that de-repression of retrotransposon LINE-1
or L1, which accounts for 17 percent of the human genome, is involved in inflammation and
degeneration of both cartilage joint and brain tissues during aging. We discovered that L1
activation is sex dependent in both mouse OA model and human OA patients by single-cell
transposable element (sc-TE) RNAseq analysis. The scTE methodology that we have developed
to study the relationship between L1 and cartilage joint degeneration can be used to determine
the sex-dependent, cause-effect relationship between L1 and AD. The scientific goal of this
project is to determine the molecular mechanisms underlying sex-difference in AD
pathogenesis. The innovative hypothesis is that females are more susceptible to early-onset and
progression of AD during aging because L1 activation is more prevalent in female CNS cell
lineages, which leads to cell senescence, inflammation, and degeneration. This hypothesis will
be tested through two aims as follows. Aim 1: Characterize and compare aging induced L1
activation patterns in the CNS between male and female in an AD transgenic mouse model with
scTE RNAseq. It will establish whether sexual dimorphism of AD progression is associated with
sex-dependent activation of L1 in a CNS cell lineage (neuronal, microglial, and astrocyte) in a
mouse AD model. Aim 2: Characterize and compare L1 activation patterns in the CNS between
male and female human AD patients with scTE RNAseq. It will correlate sexual dimorphism of
AD pathogenesis with sex-dependent activation of L1 in a CNS cell lineage of human AD patients.
The impact of this study is that it will establish whether L1 retrotransposon activation in the CNS
can be a target for sex-specific treatment of AD. 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:** 10939703
- **Project number:** 3R01AG080141-02S1
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** QIAN CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 3
- **Project period:** 2023-01-15 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939703

## Citation

> US National Institutes of Health, RePORTER application 10939703, Single-Cell Transposon Activation in the CNS during AD Progression: Sex-dependent Mechanisms (3R01AG080141-02S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10939703. Licensed CC0.

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