Somatostatin-evoked Aß catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway.
Mol Psychiatry
; 27(3): 1816-1828, 2022 03.
Article
en En
| MEDLINE
| ID: mdl-34737456
ABSTRACT
Alzheimer's disease (AD) is characterized by the deposition of amyloid ß peptide (Aß) in the brain. The neuropeptide somatostatin (SST) regulates Aß catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here, we identified α-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (KATP) 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 KATP channel subtype that modulates NEP activity, resulting in the Aß levels altered in the brain. Pharmacological intervention targeting the particular KATP channel attenuated Aß 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 KATP channel and NEP activation, and give new insights into alternative strategies to prevent AD.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos beta-Amiloides
/
Enfermedad de Alzheimer
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Mol Psychiatry
Asunto de la revista:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón