Hepcidin attenuates amyloid beta-induced inflammatory and pro-oxidant responses in astrocytes and microglia

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.CONICYT, ACT 1114, 21100165, 24120933 / FONDECYT, 1130068 / Investissements d'avenir ANR-10-IAIHU-06, ANR-11-INBS-0011-NeurATRI