Neuronostatin (NST) is an endogenous peptide hormone, it has the ability to improve oligomeric Aβ (oAβ)-induced cognitive impairments and increase blood glucose levels in mice. However, the relationship between NST and oAβ regarding brain glucose metabolism has not yet been established. The present study defined the contributions of NST and oAβ in the brain glucose metabolism in mice. It was found that i.c.v. co-administration of NST (3 nmol/mouse) and oAβ (1 nmol/mouse) decreased the mRNA expressions of glucose-6-phosphate dehydrogenase and phosphofructokinase. The treatments were observed to reduce ATP production and the enzyme activities of glucose-6-phosphate dehydrogenase and hexokinase in both the cortex and hippocampus. Simultaneously, co-injection of NST and oAβ inhibited the mRNA and protein expression of glucose transporters GLUT3 and GLUT1 in the cortex and hippocampus. NST promoted the oAβ-induced decreased the cortical NeuN staining, while oAβ increased the levels of NST in both the cortex and hippocampus. I.c.v. co-administration of NST and oAβ led to increase the levels of GPR107 expression and the phosphorylation of PKA, Akt, PERK and eIF-2α in the cortex. These findings suggest that NST promoted oAβ-induced dysfunctional glucose metabolism through the GPR107/PKA/Akt signaling pathway and PERK/eIF2α axis in the brain, which thus contributes to metabolic dysfunction and Alzheimer's disease (AD) pathophysiology.
Keywords: Aβ1-42; Glucose transporters; Glucose-6-phosphate dehydrogenase; Hexokinase; Neuronostatin; Phosphofructokinase.