# Age dependent EP receptor signaling in neuroinflammation and Alzheimer's disease

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $467,500

## Abstract

Prostaglandins (PGs), cyclooxygenase (COX) derived metabolites of arachidonic acid, mediate an array of
physiologic functions including inflammation and oxidative stress. Epidemiological studies demonstrate that
prolonged use of Non-Steroidal Anti-inflammatory Drugs (NSAIDs), which inhibit COX action, reduce the
incidence of Alzheimer’s Disease (AD). Paradoxically, administration of NSAIDs in older populations increased
Aβ42 accumulation and dementia risk. The driving force of this proposal is to reconcile these findings. The
physiological effects of the COX metabolite PGE2 are mediated by four receptors, designated the E-Prostanoid
(EP) receptors EP1 to EP4. EP receptors, primarily via EP3, mediate the pro-inflammatory response through
the generation of reactive oxygen species (ROS), highly reactive levuglandins, and the activation of the
immune-inflammatory response. Alzheimer’s disease (AD), is associated with increases in oxidative stress,
and mice with an EP3 receptor knockout display a decrease in several markers of ROS generation. The EP3
receptor is unique among the prostaglandin receptors in that multiple splice variants exist. In mouse, three
variants α, β, and γ have essentially similar ligand binding properties, but differ in aspects of signal
transduction. One of the most relevant differences among splice variants is the relative constitutive, agonist
independent, activity. Our hypothesis is that expression of the constitutively active splice variant of EP3, EP3γ,
increases with age. EP3γ signals in the absence of PGE2 ligand and thus is insensitive to the action of
NSAIDs. The hypothesis to be tested in this application is that EP3 receptors regulate inflammation and ROS
generation, accelerating AD in an increasingly ligand independent manner. We further hypothesize that in
aging individuals, a shift to constitutively active EP3γ renders NSAID inhibition of PG production ineffective and
possibly detrimental. To test our hypothesis, we propose the following Specific Aims: Specific Aim 1. To
determine changes in EP3 receptor splice variant expression with age. We will assess expression in
tissues including the brains of APPSwe-PS1DE9 (APP/PSEN1) mice and WT controls on the C57BL/6
background. We hypothesize that EP3γ expression will increase over time and predominate in older mice. We
expect that inflammatory markers will increase in parallel with EP3γ expression and become refractory to
NSAID treatment. To test this hypothesis in Specific Aim 2 We will determine whether the inflammatory
response to NSAID treatment or EP3 receptor blockade varies with age and EP receptor expression.
We hypothesize that the increase in inflammatory markers will be blunted by NSAID treatment in mature-adult
but not old mice. Proposed studies will assess whether EP3γ expression is increased with aging and whether
EP3 activity can be targeted in treatment and/or prevention of AD.

## Key facts

- **NIH application ID:** 9874856
- **Project number:** 1R21AG065859-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RICHARD M. BREYER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,500
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874856

## Citation

> US National Institutes of Health, RePORTER application 9874856, Age dependent EP receptor signaling in neuroinflammation and Alzheimer's disease (1R21AG065859-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9874856. Licensed CC0.

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