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

TitleAdiponectin suppresses amyloid-β oligomer (AβO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-kB signaling pathway
Authors
KeywordsAlzheimer’s disease
Adiponectin
Microglia
Neuroinflammation
Issue Date2019
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.jneuroinflammation.com/home/
Citation
Journal of Neuroinflammation, 2019, v. 16 n. 1, article no. 110 How to Cite?
AbstractBackground: 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.
Persistent Identifierhttp://hdl.handle.net/10722/271244
ISSN
2018 Impact Factor: 5.7
2015 SCImago Journal Rankings: 2.538
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorJian, M-
dc.contributor.authorKwan, JSC-
dc.contributor.authorBunting, M-
dc.contributor.authorNg, RCL-
dc.contributor.authorChan, KH-
dc.date.accessioned2019-06-24T01:06:07Z-
dc.date.available2019-06-24T01:06:07Z-
dc.date.issued2019-
dc.identifier.citationJournal of Neuroinflammation, 2019, v. 16 n. 1, article no. 110-
dc.identifier.issn1742-2094-
dc.identifier.urihttp://hdl.handle.net/10722/271244-
dc.description.abstractBackground: 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.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.jneuroinflammation.com/home/-
dc.relation.ispartofJournal of Neuroinflammation-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAlzheimer’s disease-
dc.subjectAdiponectin-
dc.subjectMicroglia-
dc.subjectNeuroinflammation-
dc.titleAdiponectin suppresses amyloid-β oligomer (AβO)-induced inflammatory response of microglia via AdipoR1-AMPK-NF-kB signaling pathway-
dc.typeArticle-
dc.identifier.emailKwan, JSC: jsckwan@hku.hk-
dc.identifier.emailNg, RCL: royclng@hku.hk-
dc.identifier.emailChan, KH: koonho@hku.hk-
dc.identifier.authorityNg, RCL=rp02376-
dc.identifier.authorityChan, KH=rp00537-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12974-019-1492-6-
dc.identifier.pmid31128596-
dc.identifier.pmcidPMC6535190-
dc.identifier.scopuseid_2-s2.0-85066413582-
dc.identifier.hkuros298052-
dc.identifier.hkuros298373-
dc.identifier.volume16-
dc.identifier.issue1-
dc.identifier.spagearticle no. 110-
dc.identifier.epagearticle no. 110-
dc.publisher.placeUnited Kingdom-

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