期刊
JOURNAL OF NEUROCHEMISTRY
卷 142, 期 1, 页码 140-152出版社
WILEY
DOI: 10.1111/jnc.14005
关键词
astrocytes; hepcidin; inflammation; microglia; oxidative damage; beta-amyloid
资金
- CONICYT [ACT 1114, 21100165, 24120933]
- FONDECYT [1130068]
- Investissements d'avenir [ANR-10-IAIHU-06, ANR-11-INBS-0011-NeurATRIS]
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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