# Mechanisms of blood-brain barrier deterioration in vascular cognitive impairment and Alzheimers disease

> **NIH NIH F99** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $48,974

## Abstract

Project Summary/Abstract
With our expected lifespans increasing, the rapidly expanding aging population is bringing an increased
prevalence of dementia, including Alzheimer’s disease (AD) and vascular cognitive impairment (VCI). However,
there are still no neuroprotective medicines for treating patients with these conditions. AD and VCI are the most
common types of dementia and impose a huge socioeconomic burden as well as devastating impacts on the
lives of patients and their caregivers. Both of these forms of dementia are characterized by deterioration of the
neurovascular unit that forms the blood-brain barrier (BBB), which in many cases even precedes the onset of
cognitive deficits. Unfortunately, however, the mechanisms of BBB deterioration in AD and VCI are unclear. As
a result, there are no therapies to protect the BBB. In my thesis work, I have established that the prostaglandin
degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is pathologically elevated in both
human AD and VCI in human patients. I have also shown that the enzymatic activity of 15-PGDH in the brain is
increased in the 5xFAD mouse model of AD, as well as normal aging. Importantly, I have established that
pharmacologic and genetic inhibition of 15-PGDH in 5xFAD mice shows robust protection against BBB
deterioration and other AD-related pathology, including cognitive deficits, impaired neurogenesis, and axon
degeneration, independently of amyloid β pathology. I have also found that of the prostaglandins, prostaglandin
D2 (PGD2) is most prominently elevated in the brain by 15-PGDH inhibition in 5xFAD mice. Therefore, I
hypothesize that PGD2 is responsible for 15-PGDH inhibition-mediated protection of the BBB, and that this is
related to improved endothelial cell barrier function. During the F99 portion of my proposal, I will evaluate whether
15-PGDH inhibition also protects from BBB deterioration in the high fat diet mouse model of VCI. I will utilize
innovative 2-photon microscopy in vivo imaging and electron microscopy to determine the trajectory of BBB
deterioration, as well as test the protective efficacy of 15-PGDH inhibition. I will also determine whether PGD2
mediates the protective effect both in vivo and in vitro, as previous literature suggests a role of PGD2 in
increasing endothelial cell barrier function. During the K00 phase, I will expand my BBB research by investigating
the interaction between perivascular macrophages (PVMs) and endothelial cells in the brain in Dr. Chenghua
Gu’s laboratory. I will utilize an innovative cre-recombinase system to specifically target PVMs in the brain and
investigate altered glucose metabolism in PVMs and transcriptomic profiling in both PVMs and endothelial cells,
as a function of AD-related risk factors. Then, I will test how this altered metabolism in PVMs interacts with
endothelial cells to initiate BBB deterioration. Successful completion of this study will provide new perspectives
of how the BBB deteriorates...

## Key facts

- **NIH application ID:** 10932889
- **Project number:** 5F99AG083111-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Yeo Jung Koh
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-11 → 2025-05-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932889

## Citation

> US National Institutes of Health, RePORTER application 10932889, Mechanisms of blood-brain barrier deterioration in vascular cognitive impairment and Alzheimers disease (5F99AG083111-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10932889. Licensed CC0.

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