Abstract
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 (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 Aβ levels altered in the brain. Pharmacological intervention targeting the particular KATP 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 KATP channel and NEP activation, and give new insights into alternative strategies to prevent AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid β peptide (Aβ)
We previously showed that somatostatin (SST), a neuropeptide known as a somatotropin-release inhibiting hormone [14], regulates Aβ42 levels in the brain via the upregulation of NEP [15]
Identification of ENSA as a regulator of NEP activity in vitro We previously developed a method for measuring NEP activity in the co-culture system composed of cortical/hippocampal and basal ganglia neurons, which contain both SSTR1 and SSTR4 [22]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid β peptide (Aβ). The identification of pathogenic mutations in the APP, PSEN1, and PSEN2 genes supports the amyloid cascade hypothesis underlying the etiology of AD [1], and verify that these mutations cause early-onset AD due to the abnormal production and accumulation of toxic Aβ species such as Aβ42 and Aβ43 [2, 3]. Gene therapeutic approaches in mice using adeno-associated virus carrying MME gene reduced amyloid deposition and alleviated abnormal memory function [11, 12]. A meta-analysis of genomewide association studies identified a variant in the MME gene, which leads to a change in the amino acid sequence, as a risk factor for AD, implying the potential significance of NEP in the etiological processes underlying AD development [13]
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