# Exercise-Induced Mitophagy In Hippocampal Neurons Against AD

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $564,602

## Abstract

ABSTRACT
Alzheimer's disease (AD) is a devastating neurodegenerative disease with no cure that affects >50 millions of
people worldwide. Emerging evidence supports that accumulation of damaged/dysfunctional mitochondria in the
central nervous system is an early, central pathology. Reactive oxygen species (ROS) produced by dysfunctional
mitochondria cause oxidative damages to proteins, lipids and DNA and exacerbate the key pathologies of
amyloid-β (Aβ) accumulation and hyperphosphorylation of Tau protein in a vicious cycle. In stark contrast,
endurance exercise (i.e., running) or resistance exercise (i.e., weightlifting) have significant preventive and
therapeutic impacts on AD. However, the underlying mechanisms are poorly understood. AMP-dependent
protein kinase (AMPK), a master energy sensor, has emerged as a promising regulator underlying the superb
benefits of exercise. AMPK is primarily expressed in neurons in the hippocampus, and its activity is reduced in
animal models of AD. Importantly, endurance exercise restores AMPK activity with reduced Aβ deposition along
with restored spatial learning and memory. A promising but untested mechanism is exercise-induced mitophagy,
a selective degradation of damaged/dysfunctional mitochondria under the control of AMPK and its downstream
unc-51-like autophagy activating kinase (Ulk1), resulting in improved mitochondrial quality. We hypothesize that
endurance and/or resistance exercise promotes AMPK-Ulk1 activation and mitophagy, hence removing
damaged/dysfunctional mitochondria in adult hippocampal neurons and preventing neurodegeneration
and cognitive decline in AD. To test this hypothesis, we propose:
1. To determine whether AMPK-Ulk1 activation is required for exercise-mediated protection against AD.
2. To ascertain whether AMPK activation is sufficient to protect against AD.
The proposed studies are hypothesis-driven and supported by previously published and preliminary findings with
strong scientific premises. We have also developed unique exercise and genetic models along with mitochondrial
reporter mice to address the importance and regulation of exercise-induced mitophagy against AD. The findings
will pave the way for developing effective therapeutics targeting AMPK and mitophagy for AD.

## Key facts

- **NIH application ID:** 10465751
- **Project number:** 1R01AG077783-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Zhen Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $564,602
- **Award type:** 1
- **Project period:** 2022-05-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465751

## Citation

> US National Institutes of Health, RePORTER application 10465751, Exercise-Induced Mitophagy In Hippocampal Neurons Against AD (1R01AG077783-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10465751. Licensed CC0.

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