# Exploring irisin as a novel target for Alzheimer's Disease

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $210,000

## Abstract

PROJECT SUMMARY/ABSTRACT
This application titled “Exploring irisin as a novel target for Alzheimer’s Disease” is submitted in response to NIH
PAR-16-042: Drug Discovery for Nervous System Disorders (R21). Neurological impairment caused by
neurodegenerative diseases, such as Alzheimer’s disease (AD), is a major and growing health burden. Exercise
has been shown in human studies and animal models to be neuroprotective in AD. AD is associated with an
increased Amyloid beta (Aβ)-burden, impaired hippocampal neurogenesis, and cognitive decline. Exercise
reduces the Aβ-burden, restores neurogenesis, and improves cognitive function in AD mouse models.
Understanding the underlying molecular mechanism of these neuroprotective effects of exercise has the
potential for developing innovative therapeutic approaches for this disorder. Our previously published data
identified the novel exercise hormone FNDC5 (fibronectin-domain III containing 5) and its secreted form irisin as
a prime candidate to mediate part of the neuroprotective effects of exercise. We have shown that irisin is an
exercise-induced hormone in mice and humans that mediates (part of) the beneficial effects of exercise on the
brain. Notably, the elevation of circulating irisin levels was sufficient to induce the expression of the important
neurotrophin Bdnf and other neuroprotective genes in the hippocampus. Furthermore, the addition of
recombinant irisin to a three-dimensional (3D) human neural cell culture model of AD reduced neuronal cell
death. However, further mechanistic studies on how irisin is neuroprotective are required before irisin could be
used therapeutically to treat cognitive decline in AD. Based on these data, we hypothesize that irisin has
neuroprotective effects in AD models in vivo and in vitro. The objective for this proposal is to rigorously test this
hypothesis by integrating an in vitro 3D human neural cell culture model of AD and an in vivo transgenic mouse
model of AD and using mechanistic molecular techniques, morphological studies, and behavioral testing. We
will achieve this objective by addressing (Aim 1) whether irisin is neuroprotective in vitro using a 3D human
neural cell culture model of AD and (Aim 2) whether irisin is neuroprotective in vivo using a transgenic mouse
model of AD. Successful completion of these experiments will provide a better understanding of the molecular
mechanisms whereby exercise provide neuroprotection in neurodegenerative diseases. In addition, it
establishes a framework for how irisin could be used as a therapeutic to treat AD.

## Key facts

- **NIH application ID:** 9919511
- **Project number:** 5R21AG062904-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** SE HOON CHOI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $210,000
- **Award type:** 5
- **Project period:** 2019-05-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919511

## Citation

> US National Institutes of Health, RePORTER application 9919511, Exploring irisin as a novel target for Alzheimer's Disease (5R21AG062904-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9919511. Licensed CC0.

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