Iron entry in neurons and astrocytes: a link with synaptic activity

Codazzi, Franca; Pelizzoni, Ilaria; Zacchetti, Daniele; Grohovaz, Fabio

doi:10.3389/fnmol.2015.00018

Cited by 76 publications

(68 citation statements)

References 54 publications

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“…As astrocytes have been associated with the regulation of brain iron homeostasis, specifically by buffering extracellular iron changes at the synaptic cleft (Codazzi et al . ), the observed increase in astrocyte immunoreactivity could be a physiological response of astrocytes to increased intracellular iron levels induced by hepcidin down‐regulation of FPN1.…”

Section: Discussionmentioning

confidence: 81%

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

Urrutia

Hirsch

González-Billault

et al. 2017

Journal of Neurochemistry

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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.

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Section: Discussionmentioning

confidence: 81%

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

Urrutia

Hirsch

González-Billault

et al. 2017

Journal of Neurochemistry

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“…We demonstrated an effect of iron concentration on BOLD response to increasing cognitive challenge, in a large contiguous cluster spanning the putamen, caudate nucleus and a portion of inferior frontal gyrus. Prominent age-related iron accumulation in astrocytes (Connor et al 1990;Schipper 2012;Ward et al 2014) diminishes neural signaling (Codazzi et al 2015), which could underlie alterations in brain function as measured via fMRI. Further, iron related alterations in BOLD modulation predicted poorer cognitive performance on an executive function composite construct, suggesting that this ironrelated alteration of BOLD response exerts a meaningful effect on cognition.…”

Section: Discussionmentioning

confidence: 99%

Striatal iron content is linked to reduced fronto-striatal brain function under working memory load

Rodrigue

Daugherty

Foster

et al. 2019

Preprint

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Non-heme iron accumulation contributes to age-related decline in brain structure and cognition via a cascade of oxidative stress and inflammation, although its effect on brain function is largely unexplored. Thus, we examine the impact of striatal iron on dynamic range of BOLD modulation to working memory load. N=166 healthy adults (age 20-94) underwent cognitive testing and an imaging session including n-back (0-, 2-, 3-, and 4back fMRI), R2*-weighted imaging, and pcASL to measure cerebral blood flow. A statistical model was constructed to predict voxelwise BOLD modulation by age, striatal iron content and an age × iron interaction, controlling for cerebral blood flow, sex, and task response time. A significant interaction between age and striatal iron content on BOLD modulation was found selectively in the putamen, caudate, and inferior frontal gyrus. Greater iron was associated with reduced modulation to difficulty, particularly in middle-aged and younger adults with greater iron content. Further, iron-related decreases in modulation were associated with poorer executive function in an agedependent manner. These results suggest that iron may contribute to differences in functional brain activation prior to older adulthood, highlighting the potential role of iron as an early factor contributing to trajectories of functional brain aging.Iron and BOLD modulation 0

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“…In addition, evidence suggests that astrocytes may take up NTBI (Schipper et al, 1999;Huang, Ong, & Connor, 2004;Huang et al, 2006;Keenan, Robinson, & Bishop, 2010;Yang et al, 2012;Pelizzoni et al, 2013;Huang et al, 2014;Codazzi et al, 2015). The well-confirmed presence of DMT1 and a ferri-reductase close to DMT1 Bishop et al, 2010;Pelizzoni et al, 2012;Rathore et al, 2012 ;Urrutia et al, 2013 ;Zarruk et al, 2015) and zinc-regulated and iron-regulated transporter-like protein 14 (ZIP14) in astrocytic plasma membranes and NTBI in the CSF and IF in the brain strongly support NTBI uptake by astrocytes as a DMT1-mediated and/or ZIP14-associated process.…”

Section: (4) Iron Uptake By Astrocytesmentioning

confidence: 93%

Brain iron transport

Qian

2019

Biological Reviews

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Brain iron is a crucial participant and regulator of normal physiological activity. However, excess iron is involved in the formation of free radicals, and has been associated with oxidative damage to neuronal and other brain cells. Abnormally high brain iron levels have been observed in various neurodegenerative diseases, including neurodegeneration with brain iron accumulation, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the key question of why iron levels increase in the relevant regions of the brain remains to be answered. A full understanding of the homeostatic mechanisms involved in brain iron transport and metabolism is therefore critical not only for elucidating the pathophysiological mechanisms responsible for excess iron accumulation in the brain but also for developing pharmacological interventions to disrupt the chain of pathological events occurring in these neurodegenerative diseases. Numerous studies have been conducted, but to date no effort to synthesize these studies and ideas into a systematic and coherent summary has been made, especially concerning iron transport across the luminal (apical) membrane of the capillary endothelium and the membranes of different brain cell types. Herein, we review key findings on brain iron transport, highlighting the mechanisms involved in iron transport across the luminal (apical) as well as the abluminal (basal) membrane of the blood–brain barrier, the blood–cerebrospinal fluid barrier, and iron uptake and release in neurons, oligodendrocytes, astrocytes and microglia within the brain. We offer suggestions for addressing the many important gaps in our understanding of this important topic, and provide new insights into the potential causes of abnormally increased iron levels in regions of the brain in neurodegenerative disorders.

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Iron entry in neurons and astrocytes: a link with synaptic activity

Cited by 76 publications

References 54 publications

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

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

Striatal iron content is linked to reduced fronto-striatal brain function under working memory load

Brain iron transport

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