# Age-related repetitive element dysregulation, neuroinflammation and Alzheimer's disease

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2023 · $381,880

## Abstract

PROJECT SUMMARY
Growing evidence links transposable/repetitive element (RE) transcripts with Alzheimer’s disease (AD), but
the underlying mechanisms and disease relevance are unclear. In this project, we will test the hypothesis that
the mechanism linking RE with AD is an age-dependent, global RE transcript increase that causes age/AD-
related neuroinflammation. Our rationale is that: 1) aging is the key risk factor for AD; 2) RE transcripts derived
from structural/retroviral sequences in the genome accumulate progressively with aging; 3) RE transcripts are
prone to form double-stranded RNA (dsRNA) and/or complementary DNA (cDNA), both of which can cause
neuroinflammation (a major driver of brain aging/AD that precedes pathology); 4) aging and AD are also
linked with impairments in epigenetic control (e.g., hypo-methylation, which could facilitate RE transcription)
and quality control systems like autophagy that degrade RE transcripts (which could potentiate RE-derived
cDNA/dsRNA accumulation). Emerging data even suggest that RE-derived dsRNAs/cDNAs could spread via
extracellular vesicles (EVs), a potential non-cell-autonomous explanation for the pathology observed in AD.
These observations suggest a model that is highly consistent with the age-dependence of AD, in which global,
age-related RE transcript increases lead to RE-derived dsRNAs/cDNAs that drive neuroinflammation and AD.
In support of this idea, our preliminary data show that RE transcripts are hypomethylated in AD patients and
correlate with neuroinflammation prior to pathology, and that inhibiting RE transcript buildup in human
astrocytes/neurons may reduce inflammation. We also find evidence of RE in circulating EVs from AD patients.
Based on these observations, we propose to (Aim 1) determine if age- rather than pathology-related RE
transcript dysregulation links RE with AD by performing a large bioinformatics analysis of existing RNA-seq
data, probing for RE in human/AD brains, and profiling global methylation (whole-genome bisulfite sequencing)
in the same brains, as well as in samples from >100 subjects from a longitudinal study on brain aging,
neuroinflammation and AD. In parallel (Aim 2), we will use patient-derived astrocytes and neurons to test the
efficacy of clinically translatable treatments (e.g., methylation/autophagy activators) that reduce RE-derived
dsRNAs and cDNAs for inhibiting age/AD-related neuroinflammation, and we will identify RE that may cause
neuroinflammation by binding to cellular dsRNA and cDNA sensors (PKR and cGAS). Finally (Aim 3), we will
determine if RE transcripts induce aged/AD-like neuroinflammation and accumulate in EVs in young astrocytes
and neurons, and whether these EV-borne RE transcripts cause inflammation/toxicity in other cells. We also
will use existing samples (as described above) to determine if RE in EVs are related to markers of systemic
inflammation, neuroinflammation and AD in humans. These studies are specifically designed to ext...

## Key facts

- **NIH application ID:** 10704755
- **Project number:** 5R01AG078859-02
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Thomas LaRocca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $381,880
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10704755

## Citation

> US National Institutes of Health, RePORTER application 10704755, Age-related repetitive element dysregulation, neuroinflammation and Alzheimer's disease (5R01AG078859-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10704755. Licensed CC0.

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