# Elucidating the Roles of Transposable Elements in Alzheimer's and related dementias

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $748,271

## Abstract

Project Summary
AD is an age-related progressive neurodegenerative disorder affecting millions of Americans without effective
interventions. The gradual accumulation of neurofibrillary tangles formed by abnormal protein aggregation, such
as tau and amyloid-β (Aβ) protein, serves as the neuropathological hallmark of AD. In recent years, the role of
TAR DNA-binding protein 43 (TDP-43), a DNA and RNA-binding protein that has been heavily studied in
amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD-TDP), has drawn increasing
interest for AD pathogenesis. The pathological role of TDP-43 can be attributed to both its neurotoxicity in AD
brain caused by its increased pathological aggregation in various brain regions such as the cortex and its loss
of normal function in the central nervous system. However, the detailed mechanistic role underlying TDP-43
mediated AD progression remains elusive. One established biological role of TDP-43 is to regulate the
expression of transposon elements (TEs), highly repetitive DNA sequences that occupy more than half of human
genome. A hallmark of TEs is that they harbor a three-stranded DNA:RNA hybrid structure referred to as R-
loops, which have been linked to a wide variety of biological events, such as transcriptional regulation and
genomic stability maintenance. Recent publications, along with our preliminary data, suggest a direct role of
TDP-43 in regulating R-loop formation. Our long-term goals are to elucidate the role of TDP-43, via R-loop
regulation, for controlling TE expression in age-related neurodegeneration, and to translate our findings into
clinically relevant strategies for the improved treatment of AD. In this application, we focus on how TDP-43 loss-
of-function results in altered TE expression and leads to AD pathogenesis. Our exciting preliminary data suggest:
1) Global alteration of TE expression and associated changes of the R-loop landscape are observed in human
AD postmortem brains and are distinctive from AD mouse model; 2) Evolutionarily younger TEs show higher
expression levels and stronger R-Loop enrichment than more ancient TEs, in general, and they also harbor more
drastic TE/R-loops changes in AD brains; 3) Stable depletion of TDP-43 in neuronal cells leads to aberrant R-
loop alterations in TEs, concurrent with altered TE expression and 5hmC profiling; 4) TDP-43 directly binds to a
subset of TEs in neuronal cells which overlap with AD associated TEs, and 5) AD patient derived 3D cortical
organoids corroborate cellular and molecular phenotypes of AD, serving as an excellent human model system.
We will test the hypothesis that TDP-43 plays an important role in modulating TE expression via R-loop
regulation, and TE dysregulation due to TDP-43 loss-of-function is critical for AD pathogenesis. Findings
from these studies will provide unique mechanistic insights into the fundamental rules of TE expression
regulation by TDP-43, which has the potential to discove...

## Key facts

- **NIH application ID:** 10828435
- **Project number:** 5R01AG078937-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** PENG JIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $748,271
- **Award type:** 5
- **Project period:** 2022-08-15 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828435

## Citation

> US National Institutes of Health, RePORTER application 10828435, Elucidating the Roles of Transposable Elements in Alzheimer's and related dementias (5R01AG078937-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828435. Licensed CC0.

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