# A Forgotten Connection: Retrotransposon contribution to Alzheimer's Disease

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $374,800

## Abstract

One goal of the existing R01 is the development of a high throughput method, called
SCORE, for detection of polymorphic L1s (pL1s) retrotransposons in human DNA. Our existing
R01 does not include any studies involving analysis of Alzheimer's Disease (AD) patents'
genomes. However, such analysis would be within the scope of this R01 because pL1s and their
DNA damage are a common theme of both the funded R01 and the proposed Administrative
Supplement. The proposed research is important to AD because brains of AD patients have
increased levels of DNA breaks compared to age-matched controls with evidence supporting that
this damage leads to neuronal loss at the pre-clinical stage of AD when plaques and tangles have
not yet been formed. Thus, identification of an additional mechanism(s) underlying neuronal loss
will significantly improve our understanding of AD etiology and progress in treatment
development. Several molecular mechanisms guard against L1-associated damage. One of them
is a TRIM28-mediated suppression of L1 expression by epigenetic silencing of L1 promoters.
Although TRIM28 is expressed in neurons throughout the brain, L1 damage occurs in
hippocampus and cerebral cortex, which are the areas that are also affected in AD patients. Our
preliminary findings show that, independent of its role in suppression of L1 transcription, TRIM28
interacts with L1 proteins and stimulates L1 retrotransposition.
 We hypothesize that genomes of AD patients have more pL1s than genomes of normal
subjects, which can contribute to the neuronal loss associated with an increase in L1-associated
DNA damage, especially when combined with deregulation of TRIM28. We will test our hypothesis
through two specific aims. Aim 1 will perform a case-control study to determine the number of
pL1s in the genomes of AD patients (case) and age-matched subjects without cognitive
impairment (control). This aim will determine whether the number and/or composition of pL1s is
associated with AD. Aim 2 will determine the mechanism of TRIM28 interaction with L1 ORF2p
protein and its effect on L1 integration and DSB-formation. This aim will determine whether
TRIM28 plays a dual role in the L1 amplification cycle and the mechanism of TRIM28-associated
stimulation of L1 retrotransposition. Combined positive outcomes of these aims would justify
large-scale studies testing the utility of genomic L1 content in identifying individual risk of
developing AD and/or other age-related dementias.

## Key facts

- **NIH application ID:** 10288552
- **Project number:** 3R01AG057597-03S1
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Victoria Perepelitsa Belancio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,800
- **Award type:** 3
- **Project period:** 2018-08-18 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288552

## Citation

> US National Institutes of Health, RePORTER application 10288552, A Forgotten Connection: Retrotransposon contribution to Alzheimer's Disease (3R01AG057597-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288552. Licensed CC0.

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