# Knockin mouse models of Alzheimer's Disease

> **NIH NIH RF1** · BAYLOR COLLEGE OF MEDICINE · 2022 · $2,340,048

## Abstract

Abstract
Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The
epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid (ARA) metabolism with anti-inflammatory
activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH).
We found that sEH is predominantly expressed in astrocytes and its concentrations are elevated in postmortem
brain tissue from AD patients and 5xFAD mice. The amount of sEH expressed in the 5xFAD moue brain is
correlated with the reduction in EpFA concentrations. Using a specific small molecule sEH inhibitor, 1-
trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we reported that long-term treatment of TPPU
to the 5xFAD mice restored EpFA levels and dampened neuroinflammation. This was associated with reduced
β-amyloid pathology and improved cognitive function. Similar beneficial effects were obtained by genetic studies
using Ephx2 (gene encoding sEH) knockout mice. These findings support sEH as a potential therapeutic target
for AD. However, many questions remain to be addressed. In particular, how does the astrocytic sEH pathway
communicate with microglia to regulate neuroinflammation? What is the role of brain vasculature known to
subject to sEH regulation in this process? Whether and how sEH inhibition affect other ARA associated pathways
and their lipid derivatives? We hypothesize that AD is associated with cell-type specific changes of the sEH and
ARA metabolism in astrocytes, microglia and vascular endothelial cells, which mediate neuroinflammatory
responses through cell-intrinsic mechanisms and cell-cell communications. To test this hypothesis, we will isolate
microglia, astrocytes and vascular endothelial cells from the brains of aging and AD mouse models using our
novel Concurrent Brain cell type Acquisition (CoBrA) methodology and perform cell-type specific gene
expression and targeted lipidomics to evaluate how the ARA pathway and their lipid metabolites are changed in
response to aging and beta-amyloid or neurofibrillary tangle pathologies. Further, we will determine whether and
how sEH inhibition affords therapeutic benefit against AD pathologies and what are cell types and lipid species
that mediate these effects. Overall, these studies will provide critical information concerning the mechanism-of-
action and therapeutic targeting of sEH. It will also afford an in-depth understanding of the ARA metabolism and
identify new targets that impact AD pathogenesis.

## Key facts

- **NIH application ID:** 10445718
- **Project number:** 2RF1AG020670-21
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hui Zheng
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,340,048
- **Award type:** 2
- **Project period:** 2002-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445718

## Citation

> US National Institutes of Health, RePORTER application 10445718, Knockin mouse models of Alzheimer's Disease (2RF1AG020670-21). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10445718. Licensed CC0.

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