# Project 4: Consequences of Retrotransposable Element Activation in the Central Nervous System

> **NIH NIH P01** · BROWN UNIVERSITY · 2024 · $606,896

## Abstract

Project Summary:
 Alzheimer’s disease (AD) is a devastating neurodegenerative condition that is of increasing importance
to an aging global population. Despite decades of research, there are currently no effective treatments for AD,
and the molecular causes for sporadic forms of AD remain elusive. AD pathologies are intimately tied to the
aging brain; and understanding sources of age-related dysfunction in brain cell types are key for developing
therapeutic interventions. Increasingly, retrotransposable elements (RTEs), including the active human RTE
LINE1 (L1), are conspicuously linked to aging dysfunctions that closely resemble changes seen in AD, including
increased sterile inflammation, epigenetic instability and ultimately neurotoxicity. This presents the enticing
opportunity of pursuing L1 as a druggable target to halt runaway neuroinflammation and neurodegeneration in
AD. To this end, this proposal utilizes a trifecta of state-of-the-art human in vitro modeling systems, including
aged induced neurons (iNs), induced pluripotent stem cell (iPSC) derived astrocytes, and glial enriched
organoids to investigate the aging- and cell type-dependent consequences of L1 activation in disease relevant
cell types.
 Using a cohort of AD patients and healthy age-matched controls derived neurons, the Gage team will
test the contribution of L1 activity to two sporadic AD pathologies: neuronal senescence, and global relaxation
of chromatin. Next, the team will directly test the necessity of L1 activation for the novel finding of spontaneous
neuroinflammation in aged AD neuronal cultures. Finally, to avoid a narrow neuron-centric model of AD, we will
extend our analyses to include patient-derived astrocytes and glial-enriched brain organoids to understand the
consequences of L1 induced inflammation in other cell types of the brain and in 3D tissue specific contexts.
 This proposal provides ample opportunity for close collaborations with other participating project
members. Patient cell lines and derived neural cells can be readily provided to collaborators for targeted analyses
on a consistent set of clinically verified human samples. Sequencing and genetic analyses are paired with
collaborating strategies in both mouse and fly models of AD, providing a platform for verification of results and
future mechanistic research. The Gage team’s strategy involves L1 targeting vectors designed by collaborating
cores to ensure reliable interventions and readouts across model systems. This project, in tandem with the efforts
of collaborators, will provide the most thorough examination of consequences of L1 activation on the AD brain
to date, potentially pioneering new therapeutic strategies for this disease of immense concern.

## Key facts

- **NIH application ID:** 10759446
- **Project number:** 5P01AG051449-08
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** FRED H GAGE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,896
- **Award type:** 5
- **Project period:** 2016-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10759446

## Citation

> US National Institutes of Health, RePORTER application 10759446, Project 4: Consequences of Retrotransposable Element Activation in the Central Nervous System (5P01AG051449-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10759446. Licensed CC0.

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