Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Physical exercise is a key factor in preventing age-related cognitive decline and neurodegenerative diseases such as Alzheimer's disease (AD).
• Understanding the molecular mechanisms behind exercise's benefits is crucial for developing effective interventions.

Approach:

• Single-nucleus RNA sequencing (snRNA-seq) and ATAC sequencing (ATAC-seq) were performed on the hippocampus of APP^NL-G-F mice, a model for AD.
• Mice underwent voluntary wheel-running exercise to investigate exercise's effects on gene expression and chromatin accessibility.

Key Points:

• Exercise counteracted amyloid-induced changes in the hippocampus by modulating cell type-specific transcriptional networks.
• These networks involved activation of epidermal growth factor receptor (EGFR) and insulin signaling pathways.
• EGFR and phosphoinositide 3-kinases (PI3K) inhibition blocked exercise's cognitive benefits, while heparin-binding EGF (HB-EGF) administration improved memory in sedentary mice.

Conclusions:

• Exercise promotes neurogenesis and oligodendrocyte maturation via specific signaling pathways.
• EGF-related growth factor signaling is a druggable target for enhancing exercise-induced memory benefits.
• This study provides insights into therapeutic strategies for mitigating cognitive decline in AD.