# Project 3:  Inhibition of L1 to Alleviate Alzheimer's Disease Pathogenosis in Mouse Models

> **NIH NIH P01** · BROWN UNIVERSITY · 2022 · $572,590

## Abstract

Retrotransposable elements (RTEs) make up a large fraction of mammalian genomes. They are repressed in
young tissues but become reactivated during aging. The only family of RTEs capable of retrotransposition in the
human genome is LINE-1 (L1). L1s can inflict damage by generating mutations and illegitimate recombination
events. During the current funding cycle we, together with other PPG members, discovered another mechanism
by which L1s cause pathology – by inducing inflammation. L1 transcriptional activation leads to accumulation of
cDNA copies in the cytoplasm, where they activate cGAS-STING signaling, ultimately driving a type I interferon
(IFN-I) response. Thus, L1s act like enemies within that awaken during aging and drive age-related pathologies.
Remarkably, ‘sterile inflammation’ has emerged as a driver of multiple age-related pathologies, including
Alzheimer’s disease (AD), cardiovascular diseases, cancer and diabetes. The brain has long been considered a
‘privileged’ site for L1 activation. Levels of SIRT6 protein, one of whose functions it to repress L1 elements, are
lower in the brain of AD patients, further strengthening the link between L1 activation and AD pathology. In the
next funding cycle, we propose to test the hypothesis that silencing of L1 by genetic or pharmacological
approaches will alleviate age-related pathologies including AD. The collaborations among Projects and Cores in
this PPG will allow us to comprehensively examine the role of L1 in AD pathogenesis using our mouse models
as well as human neurons and astrocytes (Projects 1, 4). We will use three strategies to inactivate L1s: silencing
with shRNA, overexpression of SIRT6, and pharmacological inhibition with nucleoside reverse transcriptase
inhibitors. We generated two new mouse models: Annihilator mice in which L1 expression can be downregulated
by chained shRNAs, and SIRT6 overexpressing mice (SIRT6-OE). Both constructs are floxed and integrated in
the ROSA26 locus. Another approach will be to downregulate downstream inflammatory signaling by inhibiting
STING. Our Specific Aims are: (1) Test the effects of genetic or pharmacological L1 inhibition on AD pathology
in mouse models. In collaboration with Core C we will cross Annihilator and SIRT6-OE mice to MAPT and 5xFAD
models of neurodegeneration. We will also treat MAPT and 5xFAD mice with the NRTI FTC and analyze the
effect on lifespan and pathology with Project 1 and Cores B and C. (2) Determine the mechanisms responsible
for the formation of cytoplasmic L1 cDNAs in brain tissue (in collaboration with Projects 1 and 4, which will work
with human astrocytes and neurons, and Core B, who will provide technical resources). We will sequence the
cytoplasmic L1 DNA from brain tissue, determine the mechanisms of its priming, intracellular localization, and
identify binding proteins using mass spectrometry. (3) Determine the effects of STING inhibition on AD
pathogenesis. We will breed STING knockout mice and mice with ...

## Key facts

- **NIH application ID:** 10333663
- **Project number:** 2P01AG051449-06
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Vera Gorbunova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $572,590
- **Award type:** 2
- **Project period:** 2016-09-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333663

## Citation

> US National Institutes of Health, RePORTER application 10333663, Project 3:  Inhibition of L1 to Alleviate Alzheimer's Disease Pathogenosis in Mouse Models (2P01AG051449-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10333663. Licensed CC0.

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