# Project 2: Role of Retrotransposable Element Activity in Drosophila Models of Alzheimer's Disease

> **NIH NIH P01** · BROWN UNIVERSITY · 2022 · $579,746

## Abstract

The overall goals of this proposal are to exploit the Drosophila model system to determine the role of
retrotransposable elements (RTEs) in the progression of cellular dysfunction that occurs during aging and
disease, and to develop interventions that suppress RTE activity to extend healthy life span and delay the onset
and progression of diseases such as Alzheimer's Disease (AD). We hypothesize that increased activity of RTEs
with age leads to loss of cellular and organismal homeostasis in somatic cells promoting aging. This in turn
interacts with AD-related changes in chromatin and RTE activity to accelerate neurodegeneration. We will use
the powerful molecular and genetic tools, as well as the short life span of Drosophila, to determine how aging
and human AD-related proteins affect the activity of RTEs and chromatin state in the brain and identify new and
novel genes that repress RTE activity and AD-related phenotypes in order to extend healthy life span and delay
the onset and progression of fly AD. We will examine how aging affects the activity of RTEs in specific subsets
of neurons and glia, and in turn, how this affects both normal aging processes and neurodegeneration in fly AD
models. Using the Drosophila model, we will employ mutagenesis screens to rapidly identify new genes and
physiological pathways controlling RTE activity and use these genetic interventions to perform detailed
phenotypic analyses over the entire life span of the organism, something that would not be possible in humans,
and would be prohibitively expensive and time-consuming to do in mammalian models on any large scale.
The aims of this proposal are to test the hypotheses that aging and AD interact to (i) increase RTE activity and
(ii) alter chromatin and the epigenome in selective cells in the adult fly brain; and (iii) use forward genetic screens
in Drosophila to isolate new suppressors of RTE activity that extend healthy life span and delay the onset and
progression of neurodegeneration in fly AD models.
To do this we will use new methods to examine in Aim 1 how age and AD change RTE expression and
mobilization in specific subsets of neurons and glia in the adult fly brain with scRNA-seq and RTE mobilization
reporters (in collaboration with Core B and Project 4), in Aim 2 determine how age and AD change the chromatin
state and epigenome related to RTEs with sc-ATAC-seq and CUT&RUN (in collaboration with Core B and Project
4), and in Aim 3 use a novel forward genetic screen to identify new genes and physiological pathways that
suppress RTE activity in adult fly brains, resulting in extension of life span and delaying the onset and progression
of fly AD. In collaboration with Projects 1, 3, and 4 and Core C the mammalian and human homologs of these
genes and physiological pathways that suppress fly AD will be tested for their ability to delay the onset and
progression of neurodegeneration in mouse AD models and AD-related cellular phenotypes in human neurons
and gl...

## Key facts

- **NIH application ID:** 10333662
- **Project number:** 2P01AG051449-06
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** STEPHEN L HELFAND
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $579,746
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333662

## Citation

> US National Institutes of Health, RePORTER application 10333662, Project 2: Role of Retrotransposable Element Activity in Drosophila Models of Alzheimer's Disease (2P01AG051449-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10333662. Licensed CC0.

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