Chronic oral administration of apelin-receptor agonist reverses cognitive impairments and alleviates neuropathology in an Alzheimer’s disease mouse model

Abstract

Introduction: Alzheimer’s Disease (AD) is the most common cause of dementia and it is characterized by extracellular amyloid plaques, intracellular neurofibrillary tangles and neuronal loss. Numerous evidence has shown the association between neuronal insulin resistance and AD pathogenesis. Neuronal insulin resistance not only enhances the activity of J-secretase, Aβ production and deposition, but also reduces Aβ clearance, impedes microglial phagocytotic activity, and induces GSK3β-mediated Tau phosphorylation. Recent reports have shown that Apelin can increase glucose uptake by promoting GLUT4 translocation and restoring insulin sensitivity of TNFα-induced insulin resistance via activating PI3K/AKT and Erk1/2 signalling pathways. In this study, we use a novel invented Apelin receptor (APJ) agonist, CMF-019, to investigate if AD neuropathology can be ameliorated through the activation of Apelin/APJ system. Methods: 5xFAD mice, at 9-month age, were fed with either CMF-019 (50 mg/kg of weight) or corn oil daily by oral gavage for 3 months. Novel object recognition test and Morris water maze test were performed to evaluate the cognitive and memory function of CMF-019-treated 5xFAD mice (CMF-5xFAD), Corn-oil-treated 5xFAD (Veh-5xFAD) and C57BL/6N (wildtype) mice. The neuropathology of these mice was evaluated by immunohistochemistry and western blot analysis. Results: Chronic oral administration of CMF-019 significantly improved cognitive function in 5xFAD mice. CMF-5xFAD and wildtype spent more time on novel object than the Veh-5xFAD. Moreover, CMF-019 and wildtype mice have shown shorter latency (P<0.05) in the hidden platform test and spent significantly more time (P<0.01) to locate in the target quadrant in the probe test, indicating that the CMF-019 has ameliorated the learning and memory deficits in 5xFAD mice. Meanwhile, immunohistochemistry demonstrated that the intensities of Iba1 and GFAP staining were significantly decreased in the hippocampus and cerebral cortex of CMF-5xFAD when compare with that of Veh-5xFAD (P<0.01), illustrating that CMF-019 reduced microgliosis and astrogliosis. The elevated MAP2 intensity (P<0.01) in the cerebral cortex of CMF-5xFAD demonstrated greater dendritic integrity after CMF-019 treatment. Reduction of the number of Thioflavin S+ plaques (P<0.01) was also found in the hippocampus of CMF-5xFAD. These results indicated that CMF-019 alleviated the amyloid pathology in the AD mouse model. Conclusion: Chronic CMF-019 treatment improved spatial memory functions and significantly rescued dendritic impairment in 5xFAD mice. CMF-019 decreased fibrillary amyloid and reduced microglial and astrocytic activity in AD mice. Our results indicated that CMF-019 exhibited multiple therapeutic benefits towards AD and hence, chronic administration of CMF-019 could serve as a potential treatment for AD.