# Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's Disease:  The Role of Xanthine Oxidase

> **NIH NIH R56** · WEST VIRGINIA UNIVERSITY · 2020 · $518,125

## Abstract

PROJECT SUMMARY / ABSTRACT
Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia
behind Alzheimer's disease (AD), and is a frequent co-morbidity with AD. Furthermore, the deleterious effect of
vascular pathologies combined with AD pathology leads to increased likelihood of dementia. Despite the
importance of VCID, little is known about its molecular mechanisms underlying vascular and cognitive
dysfunction. This has led the NIH to prioritize studies examining vascular contributions to dementia, and its
interplay with AD. Chronic psychosocial stress is a risk factor of VCID. Our preliminary data showing that chronic
stress leads to considerable cerebrovascular and neuroinflammatory changes that have similar fundamental
changes evident in the progression of AD has led us to focus on this process. Endothelial dysfunction is a critical
determinant of vascular disease and predictor of clinical events. Xanthine oxidoreductase (XOR) is a major
source of oxidative products (hydrogen peroxide and superoxide) and uric acid. The liver is the site of greatest
XOR activity and the main source of circulating XOR activity. As such, XOR can negatively affect the vasculature.
Our preliminary data suggest that chronic stress increases XOR activity resulting in cerebrovascular dysfunction
and increased neuroinflammation leading to cognitive impairment. Our central hypothesis is that chronic stress
elevates hepatic XOR, which is released into the circulation directly causing cerebrovascular dysfunction and
the activation of neuroinflammation via a TLR4 pathway resulting in cognitive decline which accelerates
dementia/AD pathology. Aim 1 uses a liver (hepatocyte)-specific XOR conditional KO (HXdh-/-) mouse and a
liver-specific XOR overexpression tool to manipulate the XOR pathway during 8 weeks of chronic stress and to
examine the pathology of VCID. In Aim 2, we will uses the TLR4-/- mouse, along with physiological and
pharmacological approaches to manipulate the TLR4/NF-κB pathway, again in the context of chronic stress and
determine VCID pathology. In Aim 3, we will use the increase in XOR activity with chronic stress and switch its
bad oxidative products to nitric oxide by supplementing with nitrite and determine its actions on the pathology of
VCID. Complementary experiments will also examine the interaction of VCID and AD, by manipulating the XOR
pathway (using febuxostat or nitrite) and determining if we can delay the pathological progression of AD (3xTg-
AD mice). Pilot data support this hypothesis. Thus, the overall goal of these studies is to determine the etiology
of the stress-related XOR and pro-inflammatory changes in mediating VCID, and its progression to AD pathology.
The studies will fill gaps identified by the NIH regarding the need for understanding of vascular contributions to
cognitive impairment and dementia.

## Key facts

- **NIH application ID:** 10206431
- **Project number:** 1R56NS117754-01
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Paul D Chantler
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,125
- **Award type:** 1
- **Project period:** 2020-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10206431

## Citation

> US National Institutes of Health, RePORTER application 10206431, Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's Disease:  The Role of Xanthine Oxidase (1R56NS117754-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10206431. Licensed CC0.

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