Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model.
Xin LiChaozhong LiuWenbo LiYanwan DaiChaohao GuWenjun ZhouVeronica C CilibertoJing LiangKumar S UdhayaDongyin GuanZhaoyong HuHui ZhengHu ChenZhandong LiuYing-Wooi WanZheng SunPublished in: bioRxiv : the preprint server for biology (2024)
Physical exercise represents a primary defense against age-related cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD). To impartially investigate the underlying mechanisms, we conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and ATAC-seq) on the hippocampus of mice carrying AD-linked NL-G-F mutations in the amyloid precursor protein gene (APP NL-G-F ) following prolonged voluntary wheel-running exercise. Our study reveals that exercise mitigates amyloid-induced changes in both transcriptomic expression and chromatin accessibility through cell type-specific transcriptional regulatory networks. These networks converge on the activation of growth factor signaling pathways, particularly the epidermal growth factor receptor (EGFR) and insulin signaling, correlating with an increased proportion of immature dentate granule cells and oligodendrocytes. Notably, the beneficial effects of exercise on neurocognitive functions can be blocked by pharmacological inhibition of EGFR and the downstream phosphoinositide 3-kinases (PI3K). Furthermore, exercise leads to elevated levels of heparin-binding EGF (HB-EGF) in the blood, and intranasal administration of HB-EGF enhances memory function in sedentary APP NL-G-F mice. These findings offer a panoramic delineation of cell type-specific hippocampal transcriptional networks activated by exercise and suggest EGF-related growth factor signaling as a druggable contributor to exercise-induced memory enhancement, thereby suggesting therapeutic avenues for combatting AD-related cognitive decline.
Keyphrases
- growth factor
- cognitive decline
- high intensity
- epidermal growth factor receptor
- physical activity
- mild cognitive impairment
- transcription factor
- genome wide
- single cell
- tyrosine kinase
- gene expression
- mouse model
- rna seq
- resistance training
- small cell lung cancer
- type diabetes
- poor prognosis
- advanced non small cell lung cancer
- induced apoptosis
- high fat diet induced
- binding protein
- metabolic syndrome
- working memory
- bipolar disorder
- dna methylation
- body composition
- insulin resistance
- venous thromboembolism
- long non coding rna
- dna binding
- radiation therapy
- subarachnoid hemorrhage