Role of adiponectin in neuroinflammatory response of microglia in Alzheimer's disease

Abstract

Microglia activation leading to neuroinflammation plays an important role in the pathogenesis of Alzheimer’s disease (AD). Extracellular deposition of β-amyloid (Aβ) which is one of major pathological hallmarks of AD can induce microglia activation. Adiponectin (APN), a key adipokine derived from adipocyte, inhibits inflammatory response in both periphery and central nervous system (CNS). However, the mechanistic basis for APN on microglia-mediated neuroinflammation in AD are not completely understood. The aim of this study is to explore: 1) The possible mechanism of APN in neuroinflammatory response of microglia in AD in vitro study. 2) The role of APN on microglia in the pathogenesis of AD in vivo study. In vitro study, Aβ oligomers (AβO) were prepared from human Aβ42 peptide. Inflammatory response BV2 microglial cells to AβO and effects of APN were determined by iii measuring proinflammatory cytokines tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) with ELISA. Small interference RNA (siRNA) were used to knock down adiponectin receptor 1 (AdipoR1) or adiponectin receptor 2 (AdipoR2). To study the neuroprotective role of APN, HT- 22 cells were treated with conditioned medium from BV2 cells with AβO or APN, or co-cultured with BV2 cells in a transwell system. The cell viability of HT-22 cells was determined by MTT reduction. The effect of APN on phagocytic ability of AβO-exposed BV2 cells was accessed by phagocytosis assay with latex beads. In vivo study, APN-deficient AD mice (APN−/−5xFAD) were generated by crossing 5xFAD mice with APN knockout mice (APN−/−) to study the role of APN deficiency on neuroinflammatory response of microglia and deposition of Aβ plaque in AD mice at different age. The following conclusions are reached in this study: First of all, APN inhibited neuroinflammatory response of microglia induced by AβO. Secondly, AdipoR1-AMPK- NF-kB signaling pathway was involved in anti-inflammatory effect of APN on AβO-exposed microglia. Thirdly, APN deficiency exacerbated the microglial activation with increased TNFα and IL-1β levels in AD mice. Lastly, APN deficiency decreased phagocytosis of microglia and promoted Aβ plaque deposition in AD mice.