Adiponectin attenuates microglia-mediated neuroinflammation and modulates microglia phagocytosis in Alzheimer’s Disease

Abstract

OBJECTIVES: Alzheimer’s disease (AD) pathogenesis is found to be associated with microglia-mediated neuroinflammation. Adiponectin (APN), an adipocyte- derived adipokine, exerts anti-inflammatory effect in both periphery and the brain. However, the role of APN on microglia-mediated neuroinflammation in AD remains unknown. Here, we aim to determine the role of APN in microglia-mediated neuroinflammation in AD. METHODS: The BV2 microglia cells were stimulated by oligomeric Aβ (AβO) for 24h with APN. Levels of pro-inflammatory cytokines, protein expression and phagocytosis ability were determined by the ELISA, Western Blot and phagocytosis assay. We generated APN knock-out mice by crossing 5xFAD mouse model of AD (APN-/-5xFAD) to determine the impact of APN deficiency on microglia-mediated neuroinflammation in AD. RESULTS: We found that APN suppressed AβO-induced TNFα and IL-1β production via AMPK- NF-κB cascade in BV2 cells. Additionally, AdipoR1 siRNA abolished the anti-inflammatory effects of APN. APN also increased the number of phagocytosed green beads in AβO-exposed microglia. Moreover, we found that APN deficiency significantly altered microglia density in APN-/-5xFAD mice at 9-month old. Microglia reactivation is associated with upregulation of TNFα and IL-1β in cortex and hippocampus in APN-/-5xFAD mice. CONCLUSIONS: Our data show APN can inhibit AβO-induced neuroinflammation and promote microglia phagocytosis ability in BV2 cells. APN deficiency in AD increased microglia reactivation in 5xFAD, suggesting that APN is a potential therapeutic agent to inhibit neuroinflammation in AD.