Adiponectin Regulates the Polarization and Function of Microglia via PPAR-γ Signaling Under Amyloid β Toxicity

Song, Jeong Sup; Choi, Seong-Min; Kim, Byeong C.

doi:10.3389/fncel.2017.00064

Cited by 51 publications

(36 citation statements)

References 76 publications

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“…1b ). This data is consistent with a recent finding that AdipoR1 knockdown in microglial cell line BV-2 exhibited M1 polarization, pro-inflammatory phenotype, under the basal condition 31 . In summary, AdipoR1 knockdown have shown neurodegeneration-mediated memory dysfunction as well as global AD-like pathologies including insulin signalling dysfunction, proteinopathies and neuroinflammation.…”

Section: Resultssupporting

confidence: 93%

Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies

Kim

Abid

et al. 2017

Sci Rep

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Recent studies on neurodegeneration have focused on dysfunction of CNS energy metabolism as well as proteinopathies. Adiponectin (ADPN), an adipocyte-derived hormone, plays a major role in the regulation of insulin sensitivity and glucose homeostasis in peripheral organs via adiponectin receptors. In spite of accumulating evidence that adiponectin has neuroprotective properties, the underlying role of adiponectin receptors has not been illuminated. Here, using gene therapy-mediated suppression with shRNA, we found that adiponectin receptor 1 (AdipoR1) suppression induces neurodegeneration as well as metabolic dysfunction. AdipoR1 knockdown mice exhibited increased body weight and abnormal plasma chemistry and also showed spatial learning and memory impairment in behavioural studies. Moreover, AdipoR1 suppression resulted in neurodegenerative phenotypes, diminished expression of the neuronal marker NeuN, and increased expression and activity of caspase 3. Furthermore, AD-like pathologies including insulin signalling dysfunction, abnormal protein aggregation and neuroinflammatory responses were highly exhibited in AdipoR1 knockdown groups, consistent with brain pathologies in ADPN knockout mice. Together, these results suggest that ADPN-AdipoR1 signalling has the potential to alleviate neurodegenerative diseases such as Alzheimer’s diseases.

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Section: Resultssupporting

confidence: 93%

Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies

Kim

Abid

et al. 2017

Sci Rep

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“…Consistent with peripheral inflammatory studies (Satoh et al ., ; Masuda et al ., ), our data suggested that microglial M1 and M2 phenotypes are also regulated by IRF5 and IRF4, respectively. Emerging data have demonstrated the IRF5/4 signaling was implicated in neurodegenerative (Zhu et al ., ; Song et al ., ) and infectious (Takaoka et al ., ; Balkhi et al ., ; Satoh et al ., ; Xuan et al ., ) diseases, and indicated that IRF5/4 are the key determinants for macrophage polarization upon inflammatory stimuli (Al Mamun & Liu, ). The present study found the expression of IRF5/4 in ischemic microglia is up‐regulated in a time‐dependent manner that is closely correlated with M1/2 phenotype, respectively, suggesting microglia share the same mechanism as that in peripheral monocytes to respond to self‐antigens.…”

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice

Mamun

Chauhan

et al. 2018

Eur J of Neuroscience

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Microglial activation is a key element in initiating and perpetuating inflammatory responses to stroke. Interferon regulatory factor 5 (IRF5) and IRF4 signaling have been found critical in mediating macrophage pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes respectively in peripheral inflammation. We hypothesize that the IRF5/4 regulatory axis also mediates microglial activation after stroke. C57BL6 mice of 8–12 weeks were subject to a 90-minute middle cerebral artery occlusion and the brains evaluated at 24h, 3d, 10d and 30d after reperfusion. Flow cytometry was utilized to examine microglial activation and cytokine expression. RT-PCR was performed for mRNA levels of IRF5/4 in sorted microglia. Microglial expression of IRF5/4 was examined by immunohistochemistry, and brain cytokine levels were determined by ELISA. Our results revealed that the IRF5 mRNA level in sorted microglia increased at 3d of stroke; whereas IRF4 mRNA level exhibited bi-phasic increases, with a transient rise at 24h and a peak at 10d. The same pattern was seen in IRF5/4 protein colocalization with Iba-1+ cells by IHC. Intracellular levels of TNFα and IL-1β in microglia peaked at 3d of stroke, and IL-4+IL-10+ double positive microglia significantly increased at day 10. Brain levels of these cytokines were consistent with microglial cytokine changes. Worse behavior test results were seen at 3d vs. 10d of stroke. We conclude that microglia phenotypes are dynamic to ischemic stroke and IRF5/4 signaling may regulate microglial M1/M2 activation and impact on stroke outcomes.

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“…The same group also showed that globular adiponectin directly inhibits microglia pro-inflammatory profile in vivo and in vitro (Nicolas et al, 2017) in a mechanism involving AdipoR1 and NF-κB. Adiponectin also modulates microglial activation profile under Aβ toxicity in vitro , via PPARγ activation (Song et al, 2017). Further evidence for the anti-inflammatory actions of adiponectin in the CNS come from a study showing that CTRP9, an AdipoR1 agonist, attenuates neuroinflammation in a mouse model of intracerebral hemorrhage through a AdipoR1/AMPK/NFκB signaling mechanism (Zhao et al, 2018).…”

Section: Adiponectinmentioning

confidence: 98%

The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer’s Disease

2019

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Cross-talk between adipose tissue and central nervous system (CNS) underlies the increased risk of obese people to develop brain diseases such as cognitive and mood disorders. Detailed mechanisms for how peripheral changes caused by adipose tissue accumulation in obesity impact the CNS to cause brain dysfunction are poorly understood. Adipokines are a large group of substances secreted by the white adipose tissue to regulate a wide range of homeostatic processes including, but not limited to, energy metabolism and immunity. Obesity is characterized by a generalized change in the levels of circulating adipokines due to abnormal accumulation and dysfunction of adipose tissue. Altered adipokine levels underlie complications of obesity as well as the increased risk for the development of obesity-related comorbidities such as type 2 diabetes, cardiovascular and neurodegenerative diseases. Here, we review the literature for the role of adipokines as key mediators of the communication between periphery and CNS in health and disease. We will focus on the actions of leptin and adiponectin, two of the most abundant and well studied adipokines, in the brain, with particular emphasis on how altered signaling of these adipokines in obesity may lead to cognitive dysfunction and augmented risk for Alzheimer’s disease. A better understanding of adipokine biology in brain disorders may prove of major relevance to diagnostic, prevention and therapy.

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Adiponectin Regulates the Polarization and Function of Microglia via PPAR-γ Signaling Under Amyloid β Toxicity

Cited by 51 publications

References 76 publications

Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies

Suppression of adiponectin receptor 1 promotes memory dysfunction and Alzheimer’s disease-like pathologies

Interferon regulatory factor 4/5 signaling impacts on microglial activation after ischemic stroke in mice

The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer’s Disease

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