# The role of tissue nonspecific alkaline phosphatase in brain endothelial cell homeostasis

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2024 · $380,000

## Abstract

PROJECT SUMMARY
Stroke is one of the leading causes of dementia. However, the mechanisms underlying neurovascular
dysfunction and cognitive impairment post-stroke that lead to Alzheimer’s disease and Alzheimer’s disease
related dementias (AD/ADRD) remain unclear. Vascular cognitive impairment and dementia a type of ADRD
and is the second leading cause of dementia in older adults after AD. Although post-stroke cognitive
impairment (PSCI) and eventual post-stroke dementia (PSD) are now recognized as distinct upstream events
that are independent of VCID, it is also widely accepted that stroke initiates a series of neurovascular events
that either independently or dependently, contribute to the onset of VCID. The objective this supplement
application is to employ the novel mouse model in in our funded R01 application to elucidate mechanisms
underlying the pathophysiology of stroke-induced VCID. The goal of our funded R01 was to determine the role
of endothelial tissue-nonspecific alkaline phosphatase (TNAP) in neurovascular dysfunction through the lens of
sex and age in our VEcKO mouse. This mouse contains a conditional deletion of Alpl, the gene that encodes
for TNAP, under the control of the VE-cadherin promoter, i.e.VEcKO mouse. In both young (6 months) and
aged (20-24 months) mice, we have identified a novel phenotype following the induction of experimental
ischemic stroke that mimics multiple neuropathological features of VCID that include: microhemorrhages, white
matter lesions, and blood-brain barrier dysfunction. This supplement will investigate the central hypothesis that
endothelial deletion of TNAP is a novel model of VCID that results from ischemic stroke. The aims of this R01
supplement application will employ a comprehensive approach to assess the neuropathological, cognitive, and
mechanistic underpinnings of VEcKO mice as a novel model of VCID following ischemic stroke. The proposed
aims are within the scope of the funded R01 application and will require the addition of approximately 100
mice, along mice already included in the funded application, to complete the supplement aims. Aim 1 will
expand the neuropathological characterization of VCID mice to include the detection of microinfarcts using
magnetic resonance imaging (MRI) and cerebral amyloid angiopathy. Aim 2 will employ a comprehensive
cognitive behavioral assessment to evaluate the long-term impact of loss of endothelial TNAP on VCID. Aim 3
will a mechanistic approach to investigate a novel role for circulating (plasma) extracellular vesicles on brain
endothelial cell function. Aim 4 will use spatial transcriptomics to identify cortical gene expression pathways
that are implicated in the pathophysiology of VCID. This supplement will provide a framework for the
development and characterization of a novel mouse model to better understand the stroke-induced
neurovascular, cognitive, and pathophysiological mechanisms that contribute to VCID.

## Key facts

- **NIH application ID:** 10940304
- **Project number:** 3R01AG068155-04S1
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Candice Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,000
- **Award type:** 3
- **Project period:** 2021-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940304

## Citation

> US National Institutes of Health, RePORTER application 10940304, The role of tissue nonspecific alkaline phosphatase in brain endothelial cell homeostasis (3R01AG068155-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10940304. Licensed CC0.

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