# G-quadruplex DNA in senescence of the neurovascular unit

> **NIH NIH RF1** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $1,560,000

## Abstract

Project Summary
The neurovascular unit (NVU) is a functional structure that consists of endothelial cells, surrounded by an
extracellular matrix, neurons, astrocytes, and pericytes. The NVU enables regulation of regional cerebral blood
flow and nutrient delivery to the brain tissue. With aging, a structural weakening of the NVU occurs, which is also
associated with inflammatory signaling and transport deficiencies. Critically, it is not clear how neurons,
astrocytes, pericytes, and endothelial cells undergo senescence in the NVU, and whether there are differences
in senescence pathways between healthy NVU aging and NVU in Alzheimer's diseases (AD).
The G-quadruplex (G4) is a non-canonical DNA secondary structure formed by four DNA strands containing
multiple runs of guanines. G4s play important roles in DNA recombination, replication, and regulation of
transcription. In our data, we demonstrated that brain samples from aged mice contain more G4s than that of
young mice. We showed that mice treated with a small-molecule G4 stabilizer develop cognitive impairment and
accelerated brain aging. Using a heterochronic parabiosis mouse model, we also showed that the levels of G4s
are decreased in the brain of old parabiont, compared to the age-matched iso-parabiotic mice, implicating
presence of rejuvenating factors that can reverse the elevation of G4s with aging. The effect of the old parabiont
on the young partner is more pronounced (more G4s in the young), suggesting a strong negative influence of
aging factors. Importantly, in a mouse model of AD, we demonstrated that G4s are stabilized in the brains, well
before the deposition of amyloid occurs. We hypothesize that these converging lines of evidence point at а
mechanism of senescence. Thus, the primary objective of the proposed studies is to investigate G4-associated
cellular senescence in the NVU, in aging and AD. In Aim 1, we will compare G4s across cell types in the NVU.
In Aim 2, we will determine whether G4s preferentially accumulate in the NVUs of brain regions most vulnerable
to neurodegeneration. In Aim 3, we will investigate how a peripheral factor, CXCL10, contributes to NVU's G4
senescence. G4s might be a novel pathway that can be targeted to mitigate the detrimental effects of cellular
senescence in the brain.

## Key facts

- **NIH application ID:** 10044252
- **Project number:** 1RF1AG068292-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Sean P Marrelli
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,560,000
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10044252

## Citation

> US National Institutes of Health, RePORTER application 10044252, G-quadruplex DNA in senescence of the neurovascular unit (1RF1AG068292-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10044252. Licensed CC0.

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