Hepcidin attenuates amyloid beta-induced inflammatory and pro-oxidant responses in astrocytes and microglia.
JOURNAL OF NEUROCHEMISTRY(2017)
摘要
Alzheimer's disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal death. Aggregated amyloid-beta (A beta) induces inflammation and oxidative stress, which have pivotal roles in the pathogenesis of AD. Hepcidin is a key regulator of systemic iron homeostasis. Recently, an anti-inflammatory response to hepcidin was reported in macrophages. Under the hypothesis that hepcidin mediates anti-inflammatory response in the brain, in this study, we evaluated the putative anti-inflammatory role of hepcidin on A beta-activated astrocytes and microglia. Primary culture of astrocytes and microglia were treated with A beta, with or without hepcidin, and cytokine levels were then evaluated. In addition, the toxicity of A beta-treated astrocyte- or microglia-conditioned media was tested on neurons, evaluating cellular death and oxidative stress generation. Finally, mice were injected in the right lateral ventricle with A beta, with or without hepcidin, and hippocampus glial activation and oxidative stress were evaluated. Pre-treatment with hepcidin reduced the expression and secretion of TNF-alpha and IL-6 in astrocytes and microglia treated with A beta. Hepcidin also reduced neurotoxicity and oxidative damage triggered by conditioned media obtained from astrocytes and microglia treated with A beta. Stereotaxic intracerebral injection of hepcidin reduced glial activation and oxidative damage triggered by A beta injection in mice. Overall, these results are consistent with the hypothesis that in astrocytes and microglia hepcidin down-regulates the inflammatory and pro-oxidant processes induced by A beta, thus protecting neighboring neurons. This is a newly described property of hepcidin in the central nervous system, which may be relevant for the development of strategies to prevent the neurodegenerative process associated with AD.
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关键词
astrocytes,hepcidin,inflammation,microglia,oxidative damage,beta-amyloid
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