# Contribution of endothelin 1 mediated ischemic vascular dysfunction to Alzheimer's disease

> **NIH NIH F30** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $53,974

## Abstract

PROJECT SUMMARY
Healthy cerebrovascular function is required to supply adequate blood flow to metabolically active brain
regions. This process occurs through neurovascular coupling (NVC), where signaling between neurons, glia,
and vasculature triggers an increase in local blood flow. Impairments in vascular function are present in
patients with stroke and Alzheimer's disease (AD) and are commonly associated with neurological dysfunction,
hypoxia, and increased amyloid beta (Aβ) pathology. AD and ischemia are closely linked, as patients with a
history of stroke have an increased chance of developing dementia, while many AD patients show indications
of micro-infarcts. One possible cause for this connection could be vascular dysfunction, which occurs after
ischemia and is one of the earliest complications in AD. However, the mechanisms underlying ischemia-
induced vascular impairments in AD are not fully defined. In pilot studies from our lab, we find that mice
exposed to a mild ischemic injury demonstrate NVC dysfunction lasting up to 8 months, with more severe
deficits in a mouse model of AD overexpressing Aβ. This suggests that Aβ and ischemia may have additive
effects on NVC impairment. The goal of this proposal is to study the mechanism underlying this NVC
impairment and its contribution to cognitive decline and AD-related pathology.
A mutual feature of AD and ischemia is oxidative stress, which leads to increased production of the
vasoconstrictor, endothelin-1 (ET-1). Notably, ET-1 is elevated in patients with both AD and ischemia. Aβ has
also been shown to generate reactive oxygen species that promote release of ET-1. I hypothesize that after
ischemia, increase in ET-1 contributes to excess constriction, compromises NVC, and contributes to the
vascular dysfunction observed in AD. I will use an innovative mouse model of mixed dementia, in which
Tg2576 AD model mice receive a mild ischemic stroke in early mid-life. I will administer an inhibitor of
endothelin receptor A, which is responsible for ET-1-mediated constriction, for 2 months immediately after
ischemia and test whether this treatment helps retain healthy NVC and cognitive function. I will assess disease
progression cross-sectionally at 2 timepoints, immediately after treatment ends and 8 months following
treatment, to track pathological changes through aging. Specifically, I will investigate whether ET-1 contributes
to AD-associated cognitive decline (Aim 1), vascular dysfunction (Aim 2a), histopathology (Aim 2b), and
hypoxia (Aim 2c) after ischemia. I expect my findings will show that endothelin receptor A inhibition reduces
behavioral deficits, NVC impairment, histopathological markers of disease, and hypoxia, thus establishing a
role for ET-1 in ischemia-induced vascular dysfunction in AD. These results will contribute to our understanding
of chronic vascular impairment in AD and may suggest ET-1 as a viable future therapeutic target to mitigate
AD-mediated decline.

## Key facts

- **NIH application ID:** 10995783
- **Project number:** 1F30AG089943-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Simone Woodruff
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-09-30 → 2028-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10995783

## Citation

> US National Institutes of Health, RePORTER application 10995783, Contribution of endothelin 1 mediated ischemic vascular dysfunction to Alzheimer's disease (1F30AG089943-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10995783. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*