Adiponectin suppresses amyloid-β oligomer (AβO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-κB signaling pathway

Abstract

Background Microglia-mediated neuroinflammation is important in Alzheimer’s disease (AD) pathogenesis. Extracellular deposition of β-amyloid (Aβ), 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 AβO and effects of APN were studied by measuring levels of proinflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1β [IL-1β]) in cultured medium before and after exposure to AβO, 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 AβO-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 TNFα and IL-1β release induced by AβO in BV2 cells. Additionally, APN rescued the decrease of AMPK phosphorylation and suppressed nuclear translocation of nuclear factor kappa B (NF-κB) induced by AβO. 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 AβO. Moreover, pretreatment with APN inhibited the cytotoxicity of HT-22 cells co-cultured with AβO-exposed BV2 cells. Lastly, APN deficiency exacerbated microglia activation in 9-month-old APN −/− 5xFAD mice associated with upregulation of TNFα and IL-1β in the cortex and hippocampus. Conclusions Our findings demonstrate that APN inhibits inflammatory response of microglia to AβO via AdipoR1-AMPK-NF-κB signaling, and APN deficiency aggravates microglia activation and neuroinflammation in AD mice. APN may be a novel therapeutic agent for inhibiting neuroinflammation in AD. Electronic supplementary material The online version of this article (10.1186/s12974-019-1492-6) contains supplementary material, which is available to authorized users.

Adiponectin and Cognitive Decline

“…Nevertheless, the mechanism explaining the relationship between ADPN and impaired cognitive function is often related to the inflammatory cascade. More authors theorized that serum ADPN levels could indirectly influence cognitive performances through the modulation of several interrelated systemic factors and in particular the inflammation cascade [41]. Indeed, Jian et al demonstrated that ADPN suppressed inflammatory response of microglia to amyloid-β oligomer (AβO) and ADPN deficiency may aggravate microglia-mediated neuro-inflammation in AD mice [41].…”

“…The involvement of ADPN in AD is poorly understood, with divergent results showing a decrease [39,42], increase , or no significant changes [40][41][42][43][44]. However, in the past few years, several studies show the ADPN neuroprotective properties [1].…”

Links Between Adiponectin and Dementia: From Risk Factors to Pathophysiology

“…Increased NO reduces platelet aggregation and elevates vasodilation regulating cerebrovascular microcirculation. In addition, APN could suppress amyloid-β in mice (Jian et al, 2019). Waragai et al (2016) have suggested a possible positive effect of APN by finding that higher cerebrospinal fluid (CSF) level of APN is related with lower amyloid and tau burden.…”

“…Lecompte et al (2017) found that APN retained its anti-inflammatory feature in dystrophic muscle by activating the AdipoR1-AMPK-SIRT1-PGC-1αpathway in mice. Besides, Jian et al (2019) demonstrated that APN suppressed inflammatory response of microglia to amyloid-β oligomer (AβO) and APN deficiency may aggravate microglia-mediated neuroinflammation in AD mice. In patients with severe carotid stenosis, APN's negative association with glucose, insulin, and intraplaque inflammatory markers was observed (Liberale et al, 2018).…”

“…However, it has been reported that APN inhibits the inflammatory response and improve IR to indirectly reduce the production of amyloid plaques (Kamat et al, 2016). Furthermore, a study has shown that APN suppresses inflammatory response of microglia by inhibiting AβO and that APN deficiency promotes aggravation of microglia activation and deteriorates neuroinflammation in AD mice (Jian et al, 2019). Thus, it appears to be valuable to probe and perceive crosstalk of APN to AD for effective therapies.…”