Neuronostatin promotes soluble Aβ1-42 oligomers -induced spatial learning and memory impairments in mice

Neuronostatin (NST) is composed of a 13-amino acid and amidated peptide hormone encoded in the somatostatin (SST) gene, and plays an important physiological function in diverse tissues. Previous studies have shown that intracerebroventricular (i.c.v.) and intra-hippocampally administration of NST can significantly decrease the percentage of novel object exploration time in the step-down test. In this study, to define the contribution of NST to cognitive impairments induced by soluble Aβ42 oligomers (oAβ), along with the underlying mechanisms. This study used behavioral, biochemical and immunohistological methods to find that i.c.v. administration of NST (3 nmol/mouse) disrupted the ability of spatial learning and memory in mice, led to increase the levels of cAMP, GPR107 protein expression and phosphorylation of PKA at Thr197 in the cortex and hippocampus. NST promoted oAβ (1 nmol/mouse) -induced cognitive impairments, subsequently co-injection of NST and oAβ increased the levels of GPR107 expression and PKA phosphorylation, which also led to hyperactivation of GFAP in the cortex and neuroinflammation cytokines (IL-1β, IL-6 and TNFα) both in the cortex and hippocampus. Moreover, it was demonstrated that co-administration of NST and oAβ had increased the phosphorylation of Akt and GSK3β and reduced the levels of ATP and hexokinase (HK) activity in the cortex. Therefore, taken together, this study provided powerful insight into the mechanism of NST for memory impairments induced by oAβ, and may potentially serve as a promising target for future Alzheimer's disease interventions.