# Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $477,459

## Abstract

ABSTRACT
Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and
aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions
in targeted tissues, including the CNS. Myokine secretion is heavily modified by exercise, suggesting that
myokine signaling in the periphery may underlie the well document geroprotective benefits of exercise on the
brain. The following studies address muscle proteostasis, a pathway highly activated during exercise, as a
potential new regulator of the neurocognitive benefits of exercise. We have recently generated a novel
transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B
(TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the
resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the aging
CNS and also improve cognition and memory in aging mice. Enhancing muscle proteostasis also reduced
neuroinflammation and accumulation of AD-associated pathological hallmarks in plaque based and a tau-
based models of AD. We have also identified previously unreported alterations in the transcriptome of skeletal
muscle from patients with AD, as well as potential unique populations of skeletal muscle factors that may be
driving these CNS benefits. In this project, we will determine if enhanced skeletal muscle proteostasis
promotes neuroprotection against AD-associated phenotypes, and using powerful transfer learning and
computational modeling approaches, will allow for the identification and use of exercise-associated circulating
factors as new therapeutic interventions for the preservation of CNS function during AD.

## Key facts

- **NIH application ID:** 10761644
- **Project number:** 7R01AG077536-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Constanza Javiera Cortes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $477,459
- **Award type:** 7
- **Project period:** 2022-09-30 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10761644

## Citation

> US National Institutes of Health, RePORTER application 10761644, Exercise-Associated Signaling Against CNS Aging and Alzheimer's Disease (7R01AG077536-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10761644. Licensed CC0.

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