# Nutrient sensing ghrelin signaling - a novel pathogenic factor for Alzheimer’s Disease

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2021 · $378,750

## Abstract

Project Summary
 Justification of the supplement: This application is in response to NOT-AG-20-034,
which calls new research initiatives on Alzheimer's disease (AD). My funded NIA grant
(1R01AG064869), entitled “Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-
aging”, 7/1/2019- 4/30/2024, is not AD-focused. It investigates the roles of ghrelin receptor GHS-
R in macrophage reprogramming in liver and adipose tissues during aging, focusing on immuno-
metabolic regulation in peripheral tissues. Aging is associated with metabolic decline and
increased inflammation throughout the body. Emerging evidence shows that neuroinflammation
has major roles in pathogenesis of AD. In this supplement, we aim to study the role of GHS-R in
metabolic reprogramming of microglia in AD. This supplement provides a new immuno-metabolic
angle to the AD field, shedding light on a novel role of GHS-R in AD. We believe that this
supplement is within the general scope of the funded R01, but expands into an exciting new
aspect of AD which is both complementary and synergistic with the NIA funded grant.
 Scope of the supplement: We have reported that global ablation of GHS-R improves
aging metabolism and mitigates systemic inflammation in aging, showing anti-inflammatory
macrophage polarization. Microglia are the primary drivers of neuroinflammation, our preliminary
data showed that GHS-R expression in microglia is drastically increased by AD-priming endotoxin
lipopolysaccharides (LPS) and GHS-R antagonist suppresses LPS-induced inflammation in
macroglia. We hypothesize that GHS-R is a pathogenic factor for AD; GHS-R promotes pro-
inflammatory activation and polarization of microglia to exacerbate neuroinflammation in
AD. We will study microglial GHS-R deficient 5XFAD mice (Cx3cr1CreER;Ghsrflox/flox; 5XFAD) via
the following Specific Aims: Aim 1. Determine the role of microglial GHS-R on learning and
memory, neuroinflammation, and AD pathology. Aim 2. Determine the polarization state,
cellular/molecular signatures, and regulatory mechanisms of GHS-R deficient microglia in AD.
 The impact of the supplement: This supplemental funding will provide us with the much-
needed support to investigate our new hypothesis. Our unique mouse model and solid preliminary
data combined with our expertise in immunology and aging metabolism offer strong scientific
premise and high feasibility for success. We are confident that we will successfully complete the
proposed studies with the support of the award. Results from current proposal will set the stage
for a full-fledged project in further mechanistic investigation of nutrient–sensing GHS-R in AD,
which has potential to lead to novel immunotherapeutic interventions for AD.

## Key facts

- **NIH application ID:** 10285433
- **Project number:** 3R01AG064869-03S1
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** YUXIANG SUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,750
- **Award type:** 3
- **Project period:** 2019-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285433

## Citation

> US National Institutes of Health, RePORTER application 10285433, Nutrient sensing ghrelin signaling - a novel pathogenic factor for Alzheimer’s Disease (3R01AG064869-03S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10285433. Licensed CC0.

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