# Role of AgRP neurons in chronic stress-accelerated brain aging and progression of Alzheimer's disease

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2023 · $684,853

## Abstract

PROJECT SUMMARY
Chronic stress is increasingly being recognized as a risk factor for sporadic AD. Dysregulation of the
hypothalamic–pituitary–adrenal axis (HPA axis) is common in AD patients. By stimulating corticotropin-releasing
hormone (CRH) expression and glucocorticoid secretion, chronic stress exposure exacerbates Aβ and tau
pathologies and cognitive decline. AgRP neurons, located in the arcuate nucleus, co-express GABA and send
extensive projections to the paraventricular nucleus of the hypothalamus. Our recent studies have shown that
chronic stress decreases firing rates of AgRP neurons, and that stimulating AgRP neurons can reverse chronic
stress-induced behavioral deficits, including memory impairment. HPA responses to stress can also be
dampened by stimulating AgRP neurons. In addition, we provide novel preliminary data showing that aging
induces silencing of AgRP neurons. We hypothesize that chronic stress and aging converge to silence AgRP
neurons, which leads to reduced inhibitory inputs to the PVN. This weakens negative feedback and drives HPA
hyperactivity, which in turn accelerates brain aging and worsens AD pathologies. To test this hypothesis, we
propose three specific aims. In Aim 1, we will identify molecular mechanisms of chronic stress- and aging-
induced silencing of AgRP neurons. In Aim 2, we will determine whether chronic stress-induced inhibition of
AgRP neuron activity contributes to overstimulation of the HPA axis and stress-exacerbated Aβ and tau
pathologies. In Aim 3, we will determine whether age-induced silencing of AgRP neurons accelerates the
progression of Aβ accumulation and cognitive decline.

## Key facts

- **NIH application ID:** 10740580
- **Project number:** 1R01AG083841-01
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Xin-Yun Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $684,853
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740580

## Citation

> US National Institutes of Health, RePORTER application 10740580, Role of AgRP neurons in chronic stress-accelerated brain aging and progression of Alzheimer's disease (1R01AG083841-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10740580. Licensed CC0.

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