title: Hepcidin attenuates amyloid beta-induced inflammatory and pro-oxidant responses in astrocytes and microglia.
abstract: Alzheimer's disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and neuronal death. Aggregated amyloid-β (Aβ) 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 Aβ-activated astrocytes and microglia. Primary culture of astrocytes and microglia were treated with Aβ, with or without hepcidin, and cytokine levels were then evaluated. In addition, the toxicity of Aβ-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 Aβ, with or without hepcidin, and hippocampus glial activation and oxidative stress were evaluated. Pre-treatment with hepcidin reduced the expression and secretion of TNF-α and IL-6 in astrocytes and microglia treated with Aβ. Hepcidin also reduced neurotoxicity and oxidative damage triggered by conditioned media obtained from astrocytes and microglia treated with Aβ. Stereotaxic intracerebral injection of hepcidin reduced glial activation and oxidative damage triggered by Aβ 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 Aβ, 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.
authors.affiliation: Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Urrutia
authors.affiliation: Inserm, U 1127, Paris, France.|CNRS, UMR 7225, Paris, France.|Sorbonne Universités, UPMC Univ. Paris 06, UMR S 1127, Paris, France.|Institut du Cerveau et de la Moelle Epinière, ICM, Paris, France.
authors.forename: Etienne C
authors.initials: EC
authors.lastname: Hirsch
authors.affiliation: Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile.|Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.|The Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: González-Billault
authors.affiliation: Department of Biology, Faculty of Sciences, University of Chile, Santiago, Chile.
authors.forename: Marco T
authors.identifier: 0000-0002-1967-8570
authors.initials: MT
authors.lastname: Núñez
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D017077:Culture Media, Conditioned; D064451:Hepcidins / Q000494:pharmacology*; D006624:Hippocampus / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D007276:Injections, Intraventricular; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D061251:Primary Cell Culture; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D017077:Culture Media, Conditioned; D064451:Hepcidins; D015850:Interleukin-6; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42)
keywords: astrocytes; hepcidin; inflammation; microglia; oxidative damage; β-amyloid