Effects of apelin receptor agonist on neural insulin sensitivity and neuropathology in Alzheimer's disease

Abstract

Accumulating evidence has demonstrated the association between insulin resistance in the brain and Alzheimer’s disease (AD) pathogenesis. Insulin resistance has been implicated in the various pathological processes of AD, including A production, deposition, and clearance, tau hyperphosphorylation, cerebral hypometabolism, synaptic dysfunction, and neuronal cell death. It is suggested that restoring insulin sensitivity in the brain may provide therapeutically beneficial to AD patients. However, there is still no effective curation. Apelin is an endogenous peptide hormone that exhibits insulin-sensitizing, anti-inflammatory, and neuroprotective effects. Recent reports have shown that apelin can activate PI3K/Akt and AMPK signaling pathways, leading to the elevation of peripheral glucose metabolism in insulin-resistant mice. Apelin can also suppress the expression of pro-inflammatory cytokines and ameliorate neurological deficits in I cerebral ischemia/reperfusion rats. Moreover, compelling evidence has illustrated that apelin possesses neuroprotective effects against neurologic disorders, including stroke, depression, anxiety, spinal cord injury, and neurodegenerative diseases. However, the therapeutic effects of chronic apelin administration under AD pathological development remain elusive. In this study, a novel orally active apelin receptor (APJ) agonist, CMF-019, is utilized to investigate if AD neuropathology and cognitive function can be ameliorated by activating the apelin/APJ system. Pharmacokinetics study demonstrated the capacity of CMF-019 to cross the blood- brain barrier in mice after oral administration. CMF-019 enhanced insulin sensitivity in hippocampal neurons in vitro and insulin signaling activities in the hippocampus in vivo. Chronic oral administration of CMF-019 improved spatial learning and memory functions and significantly rescued dendritic impairment in 5xFAD mice. The hippocampal glucose uptake levels were modestly restored by CMF-019 treatment. Furthermore, CMF-019 reduced plaque and A levels in the hippocampus of AD mouse model. CMF-019 also exhibited anti-inflammatory effects by suppressing reactive gliosis and pro-inflammatory cytokines levels. CMF-019 activates insulin signaling molecules and phagocytic regulators in microglia cells. An increased microglial phagocytic activity to A in 5xFAD mice was observed after chronic CMF-019 treatment. These results suggest that CMF- 019 exerts insulin-sensitizing and anti-inflammatory effects that can alleviate AD pathology and improve cognitive impairment, highlighting its therapeutic potential for treating AD.