Somatostatin-evoked Aβ catabolism in the brain: Mechanistic involvement of α-endosulfine-KATP channel pathway
抄録
<jats:title>Abstract</jats:title><jats:p>Alzheimer’s disease (AD) is characterized by the deposition of amyloid β peptide (Aβ) in the brain. The neuropeptide somatostatin (SST) regulates Aβ 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 (K<jats:sub>ATP</jats:sub>) 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<jats:sub>ATP</jats:sub> channel subtype that modulates NEP activity, resulting in the Aβ levels altered in the brain. Pharmacological intervention targeting the particular K<jats:sub>ATP</jats:sub> channel attenuated Aβ 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<jats:sub>ATP</jats:sub> channel and NEP activation, and give new insights into alternative strategies to prevent AD.</jats:p>
収録刊行物
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- Molecular Psychiatry
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Molecular Psychiatry 27 (3), 1816-1828, 2021-11-04
Springer Science and Business Media LLC
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詳細情報 詳細情報について
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- CRID
- 1360576118837784192
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- ISSN
- 14765578
- 13594184
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- データソース種別
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- Crossref
- KAKEN