# Determining the role of OXR1 in aging and Alzheimer's disease

> **NIH NIH R56** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $851,414

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite identifying some of the genetic risk factors for AD, the precise etiology of most cases of Late-Onset
Alzheimer's disease (LOAD) is unknown. Subsequently, therapies to treat AD have been largely unsuccessful.
Two important risk factors for AD, aging, and diet, with aging being the greatest risk factor for AD, remain largely
ignored. Dietary restriction (DR), one of the most robust interventions to slow aging, also delays the onset of
Alzheimer’s disease (AD) in multiple models across species. We exploited the short lifespan and powerful
genetic tools in D. melanogaster to identify that mustard (mtd)/oxidative stress resistance protein 1 (OXR1)
in neurons is required for the protective effects of DR on lifespan. Importantly, we have observed that OXR1
protects against age-related neurodegeneration in fly and human-induced pluripotent stem cell (iPSC) derived
models of neurodegenerative diseases. The mechanisms by which OXR1 protects against neurodegeneration
remains unclear. We observed that inhibiting OXR1 reduces retromer proteins while enhancing retromer
function, rescues the deleterious effects of inhibiting OXR1. Furthermore, we found that alterations in OXR1 and
several retromer proteins are associated with an increased risk of AD in humans using proteomics data from
over 1000 AD patients from the Accelerating Medicines Program-Alzheimer’s Disease (AMP-AD) network. Here,
we propose to test the hypothesis that OXR1 enhances retromer function to slow aging and neurodegeneration
using fly and human iPSC models of AD. In the first aim, we will determine the mechanisms of regulation of
OXR1 and how that influences aging and age-related neuronal damage. In the second aim, we will determine
the DR-dependent role of OXR1 in enhancing retromer function and the role of retromer in mediating the
protective effects of DR. To determine the mechanism by which OXR1 enhances retromer function upon DR; we
will use proteomics to determine and characterize the protein binding partners of OXR1. In the third aim, we will
test the role of OXR1 in protecting against neurodegeneration in models of AD, and by enhancing retromer
function. We will test whether OXR1 modulates AD pathology in fly models that overexpress human tau or
amyloid β (Aβ). We will overexpress OXR1 and retromer proteins in forebrain cholinergic and cortical neuron
derived AD iPSCs and measure AD endpoints: Aβ42/40 accumulation, cell death, and electrophysiology.
Because OXR1 regulates retromer function in the fly, we will evaluate whether this regulation is conserved in
human AD-derived iPSCs and carry out omics approaches to identify key signaling pathways mediating OXR1’s
protective effects. By characterizing retromer function and protein networks regulated by OXR1 and their role in
aging and age-dependent neurodegeneration, we will provide novel targets for developing therapeutics to slow
AD-related pathologies and extend healthspan. Furthermore, we will deter...

## Key facts

- **NIH application ID:** 10461321
- **Project number:** 1R56AG070705-01A1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Lisa M Ellerby
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $851,414
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461321

## Citation

> US National Institutes of Health, RePORTER application 10461321, Determining the role of OXR1 in aging and Alzheimer's disease (1R56AG070705-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10461321. Licensed CC0.

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