One of the pathological hallmarks of Alzheimer's disease (AD) is senile plaque composed of amyloid-β peptide (Aβ) in the brain. Neprilysin (NEP) is a potent Aβ degrading enzyme. Therefore, identification of the mechanism for NEP activity may lead to development of a preventive approach for AD. Previously we showed that somatostatin (SST) regulates NEP activity. However the molecular mechanism by which SST regulates NEP in the brain is unclear. Recently, We found that cortex/hippocampus-basal ganglia communication is important to upregulate NEP upon SST stimulation. The aim of this study is elucidation of the molecular mechanism of NEP activity based on the cell-cell communication. Firstly proteomics using primary neurons treated with SST identified α-endosulfine (ENSA), an endogenous ligand for a potassium channel, as a novel NEP regulator. To investigate the function of ENSA in vivo, we generated ENSA knock out mice using CRISPR/Cas9 and found that deficiency of ENSA increased NEP activity in the brain. Finally administration of Diazoxide which is a potassium channel modulator decreased amyloid pathology in AD model mice mediated by activation of NEP. Thus, we found a novel preventive approach for AD based on the cell-cell communication.