The AE-induced nuclear translocation of p300 and the improved synaptic plasticity in APP/PS1 mice were abolished by AMPKα inhibition with dorsomorphin (AMPK inhibitor, 10 mg/kg, intraperitoneal injection).<h4>Conclusion</h4>These findings unveil a previously unrecognized ADRB2-p-AMPKα-p300 axis that AE utilizes to orchestrate chromatin remodeling, counteracting synaptic degeneration and cognitive decline in AD, providing actionable targets for exercise-mimetic therapies. Here, EP300 is linked to Mental deterioration.