Adiponectin suppresses amyloid-? oligomer (A?O)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-?B signaling pathway.

ABSTRACT:

Background

Microglia-mediated neuroinflammation is important in Alzheimer's disease (AD) pathogenesis. Extracellular deposition of ?-amyloid (A?), a major pathological hallmark of AD, can induce microglia activation. Adiponectin (APN), an adipocyte-derived adipokine, exerts anti-inflammatory effects in the periphery and brain. Chronic APN deficiency leads to cognitive impairment and AD-like pathologies in aged mice. Here, we aim to study the role of APN in regulating microglia-mediated neuroinflammation in AD.

Methods

Inflammatory response of cultured microglia (BV2 cells) to A?O and effects of APN were studied by measuring levels of proinflammatory cytokines (tumor necrosis factor ? [TNF?] and interleukin-1? [IL-1?]) in cultured medium before and after exposure to A?O, with and without APN pretreatment. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) were targeted by small interference RNA. To study the neuroprotective effect of APN, cultured HT-22 hippocampal cells were treated with conditioned medium of A?O-exposed BV2 cells or were co-cultured with BV2 cells in transwells. The cytotoxicity of HT-22 hippocampal cells was assessed by MTT reduction. We generated APN-deficient AD mice (APN^-/-5xFAD) by crossing APN-knockout mice with 5xFAD mice to determine the effects of APN deficiency on microglia-mediated neuroinflammation in AD.

Results

AdipoR1 and AdipoR2 were expressed in BV2 cells and microglia of mice. Pretreatment with APN for 2?h suppressed TNF? and IL-1? release induced by A?O in BV2 cells. Additionally, APN rescued the decrease of AMPK phosphorylation and suppressed nuclear translocation of nuclear factor kappa B (NF-?B) induced by A?O. Compound C, an inhibitor of AMPK, abolished these effects of APN. Knockdown of AdipoR1, but not AdipoR2 in BV2 cells, inhibited the ability of APN to suppress proinflammatory cytokine release induced by A?O. Moreover, pretreatment with APN inhibited the cytotoxicity of HT-22 cells co-cultured with A?O-exposed BV2 cells. Lastly, APN deficiency exacerbated microglia activation in 9-month-old APN^-/-5xFAD mice associated with upregulation of TNF? and IL-1? in the cortex and hippocampus.

Conclusions

Our findings demonstrate that APN inhibits inflammatory response of microglia to A?O via AdipoR1-AMPK-NF-?B signaling, and APN deficiency aggravates microglia activation and neuroinflammation in AD mice. APN may be a novel therapeutic agent for inhibiting neuroinflammation in AD.

SUBMITTER: Jian M 

PROVIDER: S-EPMC6535190 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature