Adiponectin deficiency exacerbated neuropathologenesis and cognitive functions in Alzheimer’s disease mice: potential application of AdipoRon as Alzheimer’s disease treatment

Abstract

Introduction: Adiponectin (APN) reduces with age and has been implicated in Alzheimer’s disease (AD). Adiponectin has insulin-sensitising and anti-inflammatory abilities. We aimed to study if (i) APN deficiency affects amyloid β (Aβ) deposition, neuroinflammation and cognitive functions in AD mice; (ii) AdipoRon alleviates AD pathologies and cognitive functions in AD mice. Methods: Transgenic mice (5xFAD) carrying familial amyloid precursor protein and presenilin mutations were used in this study. We also generated an adiponectin-deficient AD mice (5xFAD;APN-/-) by crossing 5xFAD with APN-/- mice. These mice were fed with either vehicle or AdipoRon (50 mg/kg bodyweight per day) for 3 months. Cognitive functions of these mice were investigated. Neuropathological and molecular changes in the brains were examined. Results: Adiponectin deficiency in 5xFAD mice exacerbated memory deficits, and AD pathologies. Immunostaining demonstrated that microglia was reactivated but its phagocytic activity to Aβ was reduced in 5xFAD;APN-/- mice. Pro-inflammatory cytokine levels were elevated in the brain. Liquid chromatography–tandem mass spectrometry analysis confirmed that AdipoRon can cross the blood-brain barrier. AdipoRontreated 5xFAD and 5xFAD;APN-/- mice showed reduction of Aβ deposition in the cortex and hippocampus. AdipoRon also reduced generation of other cleavage products in amyloidosis. AdipoRon can suppress neuroinflammation, glial activation and resume the phagocytic activity of microglia. Mice treated with AdipoRon demonstrated increased activation of insulin signalling and insulin sensitisation. Lastly, AdipoRon reversed neuronal and dendritic spines reduction as well as cognitive functions in both 5xFAD and 5xFAD;APN-/- mice. Conclusion: In summary, our results demonstrated that APN deficiency exacerbated AD pathologies and neurodegeneration. Oral administration of AdipoRon can reverse cognitive impairments and AD pathologies by insulin sensitisation, demonstrating its therapeutic potential to treat AD.