CMF-019 elevates neuronal insulin sensitivity: an implication of therapeutic potential of Alzheimer’s disease

Abstract

Introduction: Increasing evidence has demonstrated the association between neuronal insulin resistance and Alzheimer’s Disease (AD) pathogenesis. Neuronal insulin resistance not only enhances the activity of γ-secretase, A β production and secretion, but also induces the activation of GSK3β, which associates with Tau phosphorylation and aggregation. Recent studies have reported that Apelin can increase glucose uptake by promoting GLUT4 translocation and restore insulin sensitivity of TNFα-induced insulin resistance via activating PI3K/AKT and ERK1/2 signalling pathways. Hence, we will study if a novel invented Apelin receptor (APJ) agonist, CMF-019 can restore the neuronal insulin sensitivity and its potential effects as a therapeutic treatment of AD. Methods: For in vitro study, insulin-induced insulin resistance (IR) hippocampal cells (HT22) were pretreated with CMF-019 for 2 hr and cultured with 10 nmol/L insulin for 30 min. Insulin-signalling molecules and its corresponding phosphorylation were measured by western blot analysis. For in vivo study, the pharmacokinetics of CMF-019 was quantitatively determined in the mice plasma and brain after feeding each mouse orally with CMF-019. Results: The results showed that CMF-019 pretreatment alleviated the insulin sensitivity of insulin-induced IR HT22 cells by increasing the level of Akt phosphorylation. However, the level of pERK1/2 did not show any significant difference upon CMF-019 pre-treatment. CMF-019 was able to be detected by the LC-MS/MS in the plasma and the brain of CMF-019-oral administrated mice. Conclusion: APJ agonist, CMF-019, elevated insulin sensitivity through PI3K/AKT activation, but not ERK1/2 signalling pathway. In addition, the penetration of CMF-019 across the blood-brain-barrier may implicate the therapeutic potential of CMF-019. Acknowledgement: This research is supported by Health and Medical Research Fund (06172306).