# FNDC5/irisin as a molecular mediator of exercise benefits in cognitive function

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $473,560

## Abstract

PROJECT SUMMARY/ABSTRACT
Neurological impairment caused by aging or neurodegenerative diseases, such as Alzheimer’s disease (AD) is
a major and growing health burden. Despite best efforts, traditional approaches to develop effective therapies
have been largely unsuccessful. Interestingly, studies in both human subjects and animal models have shown
that physical activity, especially endurance exercise, can improve cognitive function, mainly learning and
memory, in part by enhancing adult neurogenesis in the hippocampus. Recent studies have highlighted the
importance of secreted factors in cell-to-cell and cross-organ talks in exercise. The secreted factors that
mediate the cognitive benefits of exercise represent very attractive drug targets.
Our previously published data identified the novel exercise hormone irisin, the cleaved and secreted from of
FNDC5 (fibronectin-domain III containing 5), as a prime candidate contributing to the cognitive benefits of
exercise. Based on this preliminary data, we hypothesize is that FNDC5, through its secreted form irisin,
acts as a critical regulator linking exercise to adult hippocampal neurogenesis resulting in
improvements in cognitive function. Our goal is to rigorously test this hypothesis by integrating mechanistic
molecular techniques, functional and morphological studies, and behavioral testing in genetic mouse models.
We will achieve this goal by addressing the following three Specific Aims: In Aim 1, we will determine whether
muscle-derived irisin is required for exercise-induced improvement in cognitive function. In Aim 2, we will test if
irisin is the active form to mediate the beneficial effects of exercise. In Aim 3, we will elucidate whether
peripheral elevation of irisin is sufficient to improve cognitive function in aging mouse models.
Successfully completing these experiments will provide a better understanding of the molecular mechanism
whereby exercise affects adult hippocampal neurogenesis and improves cognitive function. In addition, this
project will establish a framework for potentially using irisin to treat cognitive decline in aging or AD.

## Key facts

- **NIH application ID:** 10366759
- **Project number:** 1R01NS117694-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Christiane D. Wrann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $473,560
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366759

## Citation

> US National Institutes of Health, RePORTER application 10366759, FNDC5/irisin as a molecular mediator of exercise benefits in cognitive function (1R01NS117694-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10366759. Licensed CC0.

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