Alzheimer's disease is a progressive neurodegenerative disease characterized by the deposition of amyloid β peptide, but given the lack of clinical efficacy of amyloid β inhibitors, this is increasingly disputed.
Yet neprilysin-deficient knockout mice exhibit both Alzheimer's-like behavioral alteration and beta-amyloid deposition in the brain. Since neprilysin is considered to be the step limiting the rate of degradation of beta-amyloid, it has been considered as a potential therapeutic target.
Scientists have previously shown that somatostatin, a neuropeptide, regulates Aβ42 levels in the brain via upregulation of neprilysin. Somatostatin mRNA levels are significantly decreased with aging, especially in Alzheimer's disease. This suggests that the aging-induced downregulation of somatostatin expression may be a trigger for amyloid β peptide pathology in late-onset Alzheimer's disease.
However, the mechanism by which somatostatin signaling regulates neprilysin activity remains unclear. In the present study, the authors used in vitro and in vivo experimental paradigms to identify α-endosulfine (ENSA) as a negative regulator of neprilysin activity downstream of somatostatin signaling.
In vitro and in vivo experiments revealed that neprilysin degrades α-endosulfine (ENSA) as a substrate, suggesting that neprilysin and α-endosulfine (ENSA) form a negative feedback loop. This hypothesis is based on the fact that opioids and substance P, cell-specific ligands in monocytes and bone marrow cells, respectively, regulate neprilysin via a feedback mechanism. It is possible that amyloid β peptide and α-endosulfine (ENSA) compete against each other in neprilysin-mediated degradation, additively exacerbating this feedback loop and inducing a vicious cycle.
A selective KATP channel agonist such as diazoxide (Dz) could serve as a beneficial approach to break this vicious cycle since diazoxide is sometimes used as a drug for antihypertensive and hypoglycemic properties, and has the potential in the preclinical setting. 'improve amyloid β peptide pathology and behavioral abnormalities in Alzheimer's disease.
Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension. Diazoxide also inhibits insulin secretion by opening the ATP-sensitive potassium channel of pancreatic beta cells;
The mechanism by which diazoxide (Dz) attenuated amyloid peptide plaque deposition was not clear, however. Their results indicate that diazoxide (Dz) reduced amyloid deposition in AppNL-F mice via the regulation of neprilysin activity in the anterior cortex and the hippocampus. This regional selectivity of the action of neprilysin by diazoxide (Dz) may depend on the dopaminergic system in the brain.
The authors have therefore demonstrated a new preventive approach at the preclinical stage of Alzheimer's disease based on the function of α-endosulfine (ENSA). This negative regulator of neprilysin and of the KATP channel could be a new therapeutic target for lowering the amyloid β peptide.