# Neurovascular astrocyte dysfunction in VCID

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $374,815

## Abstract

Abstract
 Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind
Alzheimer's disease (AD). In addition, VCID is a frequent co-morbidity with AD, complicating the diagnosis and
treatment of AD for a significant proportion of AD patients. Despite its prevalence, VCID remains relatively
understudied compared to AD, and little is known about the molecular mechanisms underlying the cognitive
dysfunction resulting from cerebrovascular disease. In part, this is due to the multiple pathological processes
disrupting neurovascular networks that can result in VaD.
 We have previously shown that astrocytic end-feet are significantly impacted in the presence of
cerebral amyloid angiopathy (CAA), with decreased contact of astrocytic end-feet with the vasculature. Further,
these morphological changes in the astrocyte were associated with decreased expression of aquaporin 4,
Kir4.1 and BK channels at the astrocytic end-feet. We have developed a model of VCID through the induction
of hyperhomocysteinemia (HHcy). We have shown that this model in wildtype mice is associated with multiple
microhemorrhages, reduced blood flow, neuroinflammation and cognitive impairment. We now have intriguing
preliminary data that indicates these same pathological changes in the astrocytes that we observed with CAA
also occur in our HHcy model of VCID.
 In this research proposal we will use the HHcy model of VCID. We will test the hypothesis that
astrocyte end-foot disruption contributes to neuronal dysfunction and that the activation of MMP9 in
the HHcy model is critical to the disruption of the astrocytic end-feet. We have developed 3 specific aims.
Aim 1. Test the hypothesis that astrocytic end-foot disruption leads to neuronal dysfunction and impaired
potassium homeostasis.
Aim 2. Test the hypothesis that MMP9 is an essential mediator of astrocyte end-foot detachment from the
cerebrovasculature with VCID.
Aim 3. Test the hypothesis that astrocytic end-foot disruption is a common pathological characteristic of
cerebrovascular pathologies of VCID.

## Key facts

- **NIH application ID:** 10183340
- **Project number:** 5R01NS097722-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Donna M Wilcock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $374,815
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183340

## Citation

> US National Institutes of Health, RePORTER application 10183340, Neurovascular astrocyte dysfunction in VCID (5R01NS097722-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10183340. Licensed CC0.

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