Abstract
Impaired synaptic plasticity underlies cognitive impairment as a core pathological substrate. While aerobic exercise represents a significant non-pharmacological intervention for enhancing synaptic plasticity, its precise molecular mechanisms remain incompletely defined. This study investigated whether aerobic exercise ameliorates synaptic plasticity and synaptic loss in Apolipoprotein E homozygous knockout (APOE-/-) mice by modulating the Vascular Endothelial Growth Factor (VEGF)/Extracellular Signal-Regulated Kinase (ERK) signaling pathway to mitigate cognitive function. Eight-week-old male wild-type C57BL/6 J mice served as controls, while APOE-/- mice were randomly allocated to sedentary or exercise groups. The exercise group underwent a 12-week moderate-intensity treadmill training protocol. Following spatial learning and memory assessment via the Morris water maze (MWM) testing, analyses included HE staining, Nissl staining, Oil red O staining, Golgi staining, ELISA, Immunofluorescence, Western blot, and RNA sequencing (RNA-Seq). Results demonstrated that aerobic exercise improved spatial learning and memory impairments, attenuated cerebral amyloid-beta (Aβ) deposition, increased hippocampal and prefrontal cortical dendritic spine density, and upregulated key synaptic proteins. Subsequent RNA-Seq analysis and validation revealed the underlying mechanism: aerobic exercise activated the VEGF/ERK pathway, which in turn reduced dendritic spine loss, increased synaptic protein expression, and enhanced synaptic structural remodeling, ultimately improving cognitive function. These findings provide a novel mechanistic foundation for cognitive impairment interventions and identify promising therapeutic targets.