Pathogenic accumulation of amyloid-β (Aβ) peptide, caused by an imbalance of anabolic and catabolic activity in the brain, is believed to trigger Alzheimer’s disease (AD). Identified familial mutations on APP, PSEN1, and PSEN2 genes induce excessive production of toxic Aβ species, such as Aβ42 and Aβ43, or alter the Aβ42/40 ratio, leading to Aβ deposition in the brain (1–5). Chronic attenuation of Aβ catabolism may accelerate this Aβ deposition (6). Neprilysin (NEP) is a potent Aβ-degrading enzyme in the brain (7, 8). The expression and activity of NEP decrease with aging, particularly in patients with AD (9–12), and mice lacking the NEP (MME) gene exhibit approximately twofold Aβ levels in the brain (8). Furthermore, impaired NEP activity in APP transgenic mice is associated with high levels of toxic Aβ oligomer at synapses, which cause abnormal plasticity and learning and memory dysfunction before the deposition of Aβ plaques (13). In contrast, neuronal overexpression of NEP after the administration of an adeno-associated virus (AAV) vector carrying the MME gene in AD model mice reduces toxic Aβ oligomer levels and deposition of Aβ plaques, resulting in the rescue of aberrant learning and memory function without serious adverse effects (14). Exploring targetable elements for promoting NEP-mediated degradation of Aβ may thus be beneficial. A genome- wide association study demonstrated that specific MME variants have been identified as risk factors for AD, suggesting that NEP has an etiological significance in AD (15).
Our group has previously found that the neuropeptide somatostatin (SST) enhances NEP activity (16) and, of the five SST receptor (SSTR1–5) subtypes, SSTR1 and SSTR4 (SSTR1/4) redundantly regulate NEP (17). We have also reported that α-endosulfine (ENSA), an endogenous ligand for the adenosine 5′-triphosphate–sensitive potassium channel, modulated NEP activity downstream of SST signaling (18). In this study, we aimed to explore alternative candidates that up-regulate NEP activity independently of the SST-ENSA pathway.
