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.

Baicalin mitigates cognitive impairment and protects neurons from microglia‐mediated neuroinflammation via suppressing NLRP3 inflammasomes and TLR4/NF‐κB signaling pathway

“…A microglia‐conditioned media system was used as previously described . BV2 cells were plated in 6‐well culture plates at a density of 2 × 10 5 cells/well.…”

“…A microglia-conditioned media system was used as previously described. 18 BV2 cells were plated in 6-well culture plates at a density of 2 × 10 5 cells/well. After overnight incubation, the cells were pretreated with different concentrations of BAI for 1 hour followed by stimulation with 10 μmol/L Aβ 1-42 and 1 μg/mL LPS for 24 hours.…”

Sinomenine inhibits amyloid beta-induced astrocyte activation and protects neurons against indirect toxicity

“…It has been shown previously that amyloid beta treatment of astrocytes increases the levels of inflammatory cytokines [27]. Here we examined whether sinomenine affects the production of inflammation-related molecules from ADDL-treated astrocytic cells.…”

Hepcidin and its therapeutic potential in neurodegenerative disorders

“…The fact that LPS and E. coli infection upregulates the levels of hepcidin mRNA and/or protein in the brain shows that HAMP gene expression can also be upregulated by inflammation, as was found outside of the brain. The finding that pretreatment with hepcidin reduces Aβ treatment‐induced IL‐6 expression and secretion in astrocytes and microglia and reduces neurotoxicity and oxidative damage triggered by conditioned media obtained from Aβ‐treated astrocytes and microglia imply that hepcidin can downregulate inflammatory and prooxidant processes . Recent studies have also demonstrated that intracerebroventricular injection of LPS can upregulate hepcidin expression and also downregulate Fpn1 levels in the cortex and substantia nigra of the rat brain.…”