α-Endosulfine regulates amyloid β 42 via the modulation of neprilysin activity

The neuropeptide somatostatin (SST) regulates amyloid β peptide (Aβ) catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here we report the identification by differential proteomics of α-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (K ATP ) channel, as a negative regulator of NEP activity downstream of SST signaling. Genetic deficiency of ENSA resulted in enhanced NEP activity and decreased Aβ deposition in the brains of wild-type and Alzheimer’s disease (AD) model mice. Pharmacological intervention to increase the probability of K ATP channel opening reduced Aβ deposition in AD model mice. Our findings provide new insights into possible mechanisms to prevent AD.