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

INTRODUCTION: Physical exercise is a primary defense against age-related cognitive decline and Alzheimer's disease (AD). METHODS: We conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and snATAC-seq) on the hippocampus of mice carrying mutations in the amyloid precursor protein gene (APP(NL-G-F)) following prolonged voluntary wheel-running exercise. RESULTS: Exercise mitigates amyloid-induced changes in transcriptome and chromatin accessibility through cell type-specific regulatory networks converging on growth factor signaling, particularly the epidermal growth factor receptor (EGFR) signaling. The beneficial effects of exercise on neurocognition can be blocked by pharmacological inhibition of EGFR and its downstream PI3K signaling. Exercise leads to elevated levels of heparin-binding EGF (HB-EGF), and intranasal administration of HB-EGF enhances memory function in sedentary APP(NL-G-F) mice. DISCUSSION: These findings offer a panoramic delineation of cell type-specific hippocampal transcriptional networks activated by exercise and suggest EGFR signaling as a druggable contributor to exercise-induced memory enhancement to combat AD-related cognitive decline. HIGHLIGHTS: snRNA-seq and snATAC-seq analysis of APP(NL-G-F) mice after prolonged wheel-running. Exercise counteracts amyloid-induced transcriptomic and accessibility changes. Networks converge on the activation of EGFR and insulin signaling. Pharmacological inhibition of EGFR and PI3K blocked cognitive benefits of exercise. Intranasal HB-EGF administration enhances memory in sedentary APP(NL-G-F) mice.