# STAT3 activation in astrocytes as a driver of neurovascular dysfunction in Alzheimer's disease and related dementias

> **NIH NIH RF1** · VANDERBILT UNIVERSITY · 2022 · $2,345,579

## Abstract

Project summary
Alzheimer’s disease (AD) and related dementias (ADRD) are exacerbated by neurovascular dysfunction.
Astrocytes are key contributors to neurovascular health and blood-brain barrier (BBB) function. In response to
pathogenic stimuli, astrocytes adopt a “reactive” phenotype generally characterized by morphological changes.
Recent research has shown that reactive astrocytes can adopt a diverse spectrum of molecular identities, but
the interplay between these different subtypes of reactive astrocytes and the brain vasculature remains unclear.
Indeed, some studies have shown that reactive astrocytes negatively influence BBB function, while others have
shown that reactive astrocytes are vital to neurovascular repair after injury. Most of these studies have been
performed in the context of stroke or physical trauma, and while there are some emerging studies at single-cell
resolution on reactive astrocyte states in ADRDs, there is little to no information on how these different states
may directly contribute to neurovascular dysfunction. Herein, we propose to investigate how STAT3 activation
in astrocytes drives neurovascular dysfunction in ADRDs. In preliminary work, using thin sections from
postmortem human brain tissue, we have shown that AD patients have significantly increased numbers of
STAT3-activated astrocytes and inflamed blood vessels. In a human in vitro model of astrocytes cocultured with
brain endothelial cells, we have shown that inflammatory stimuli activate STAT3 signaling in astrocytes, which
leads to BBB disruption, and inhibition of STAT3 activation in astrocytes mitigates these outcomes. Further,
using combinations of the human in vitro model, ex vivo mouse cortical slice cultures, and in vivo manipulations,
we have shown that alpha 1-antichymotrypsin (ACT)—a STAT3-regulated serine protease inhibitor—contributes
directly to neurovascular dysfunction. Moving forward, we will build on these promising results in the following
manner. In Aim 1, we will expand our human tissue studies into larger ADRD cohorts and employ advanced
imaging techniques to quantify three-dimensional spatial relationships between STAT3-activated astrocytes and
sites of vascular damage. In Aim 2, we will inhibit STAT3 signaling in astrocytes within transgenic mouse models
of ADRD and evaluate longitudinal alterations to neurovascular dysfunction; these assessments will include
single-cell RNA sequencing to characterize molecular changes to endothelial cells along the entire vascular tree.
In Aim 3, we will causally link astrocyte-derived ACT to neurovascular dysfunction in transgenic mouse models
of ADRD, as well as characterize prospectively synergy between ACT and APOE, which have known
connections in AD and dementia risk. Collectively, outcomes from this work will define the mechanistic roles of
STAT3-activated astrocytes in neurovascular dysfunction associated with ADRD and identify potential avenues
for targeting astrocytes as an ADRD treatment...

## Key facts

- **NIH application ID:** 10562131
- **Project number:** 1RF1NS129735-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Ethan Lippmann
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,345,579
- **Award type:** 1
- **Project period:** 2022-09-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10562131

## Citation

> US National Institutes of Health, RePORTER application 10562131, STAT3 activation in astrocytes as a driver of neurovascular dysfunction in Alzheimer's disease and related dementias (1RF1NS129735-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10562131. Licensed CC0.

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