Somatostatin-evoked A beta catabolism in the brain: Mechanistic involvement of alpha-endosulfine-K-ATP channel pathway

Alzheimer's disease (AD) is characterized by the deposition of amyloid beta peptide (A beta) in the brain. The neuropeptide somatostatin (SST) regulates A beta catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here, we identified alpha-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (K-ATP) channel, as a negative regulator of NEP downstream of SST signaling. The expression of ENSA is significantly increased in AD mouse models and in patients with AD. In addition, NEP directly contributes to the degradation of ENSA, suggesting a substrate-dependent feedback loop regulating NEP activity. We also discovered the specific K-ATP channel subtype that modulates NEP activity, resulting in the A beta levels altered in the brain. Pharmacological intervention targeting the particular K-ATP channel attenuated A beta deposition, with impaired memory function rescued via the NEP activation in our AD mouse model. Our findings provide a mechanism explaining the molecular link between K-ATP channel and NEP activation, and give new insights into alternative strategies to prevent AD.