# Investigating the effect of Nurr1 ligands in Alzheimer's Disease models

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $403,750

## Abstract

ABSTRACT
 Alzheimer’s disease (AD) is a complex neurodegenerative disorder that progressively impairs
cognitive abilities (e.g. memory) due to the loss of neurons in hippocampal and cortical regions of the
brain. There are no available treatments that stop or slow the progression of AD, with the possible
exception of the recently marketed monoclonal antibody drug Aducanumab. Previously approved AD
therapeutics, which act by either inhibiting acetylcholinesterase or modulating the activity of N-methyl-
D-aspartate receptors, are symptom-modifying only and just modestly effective. Investigating
alternative therapeutic targets is an important step in the search for an effective AD therapy.
 The transcription factor Nurr1 (NR4A2) has been proposed as a novel therapeutic target for
Alzheimer’s disease (AD), as the receptor regulates the expression of genes and cellular processes
associated with the pathogenesis of AD. In particular, Nurr1 stimulates the expression of genes that
reduce oxidative stress and inhibits the expression of genes that increase neuroinflammation. Although
a few synthetic “Nurr1 agonists” have been reported in the scientific and patent literature, there is little
evidence these ligands directly activate the receptor, with the exception of recent work on the
antimalarial amodiaquine, steroidal anti-inflammatory drugs, and analogs of the endogenous Nurr1
ligand (DHI). Using an orthogonal drug development strategy, my lab has identified bona fide Nurr1
ligands that bind directly to the receptor’s ligand binding domain. Further, structural studies for three of
these ligands reveal that each stabilizes Nurr1 in a different core conformation, and cellular assays
demonstrate that each ligand regulates the expression of different genes.
 The proposed research seeks to capitalize on these findings to investigate the effect of Nurr1
ligands on the expression of genes and pathological processes associated with AD. We will determine
Nurr1 ligand effects on the transcription of genes that modulate oxidative stress and responsiveness to
inflammatory signals in cells treated with amyloid peptides and tau fibrils. In addition, we will determine
Nurr1 ligand effects on the formation and secretion of Ab fibrils and the hyperphosphorylation and
aggregation of tau protein. Successful completion of this project is expected to lay the foundation for
rationally developing new AD therapeutics targeting Nurr1.

## Key facts

- **NIH application ID:** 10499241
- **Project number:** 3R01NS108404-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Pamela Michael England
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $403,750
- **Award type:** 3
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499241

## Citation

> US National Institutes of Health, RePORTER application 10499241, Investigating the effect of Nurr1 ligands in Alzheimer's Disease models (3R01NS108404-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10499241. Licensed CC0.

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