Iron Aggravates the Depressive Phenotype of Stressed Mice by Compromising the Glymphatic System

Liang, Shangdong; Lü, Yan; Li, Zexiong; Li, Shuai; Chen, Beina; Zhang, Manman; Chen, Binjie; Ji, Ming; Gong, Wenliang; Xia, Maosheng; Verkhratsky, Alexei; Wu, Xu

doi:10.1007/s12264-020-00539-x

Cited by 29 publications

(38 citation statements)

References 14 publications

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“…However, iron overloaded astrocytes may become a trigger of neurotoxicity that contributes to the pathogenesis of age-dependent neurodegeneration, which involves iron-induced oxidative stress and mitochondrial malfunction (Dringen et al, 2007;Schipper et al, 2009). In the frontal cortex, iron dextran increases the glial fibrillary acidic protein (GFAP)-positive astroglial profiles (Liang et al, 2020), which is indicative of reactive astrogliosis (Fig. 1).…”

Section: Iron Toxicity and Neurogliamentioning

confidence: 99%

“…As shown in Fig. 2, the iron overload can impair the brain-wide glymphatic system (Liang et al, 2020), responsible for the clearance of waste proteins through a paravascular pathway (Iliff and Nedergaard, 2013). In the mice model of depression induced by chronic unpredictable mild stress (CUMS), the function of glymphatic system is suppressed by down-regulation of the expression of the astrocytic water channel aquaporin 4 (AQP4) (Xia et al, 2016).…”

Section: Iron Toxicity and Neurogliamentioning

confidence: 99%

“…In the mice model of depression induced by chronic unpredictable mild stress (CUMS), the function of glymphatic system is suppressed by down-regulation of the expression of the astrocytic water channel aquaporin 4 (AQP4) (Xia et al, 2016). Injection of iron dextran further worsens the operation of the glymphatic system and exacerbates the depressive-like behaviours induced by CUMS; in turn, this triggers neuronal apoptosis (Liang et al, 2020). Hence, the iron supplements for major depressive patients should be monitored.…”

Section: Iron Toxicity and Neurogliamentioning

confidence: 99%

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Astrocytes in heavy metal neurotoxicity and neurodegeneration

Xia

Zorec

et al. 2021

Brain Research

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Section: Iron Toxicity and Neurogliamentioning

confidence: 99%

Section: Iron Toxicity and Neurogliamentioning

confidence: 99%

Section: Iron Toxicity and Neurogliamentioning

confidence: 99%

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Astrocytes in heavy metal neurotoxicity and neurodegeneration

Xia

Zorec

et al. 2021

Brain Research

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“…Astrogliosis plays important, if not defining role in evolution of many neurological diseases 69 . Our previous experiments have shown that formation of brain deposits of iron up-regulates astroglial expression of TFR and instigates reactive astrogliosis 70 . What characterises the iron-induced reactive phenotype and what is the role of astroglial reactivity in managing excessive iron in the brain remains to be found.…”

Section: Discussionmentioning

confidence: 98%

Iron induces two distinct Ca2+ signalling cascades in astrocytes

Guan

Xia

et al. 2021

Commun Biol

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Iron is the fundamental element for numerous physiological functions. Plasmalemmal divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of ferrous (Fe2+), whereas transferrin receptors (TFR) carry transferrin (TF)-bound ferric (Fe3+). In this study we performed detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Administration of Fe2+ or Fe3+ in μM concentrations evoked [Ca2+]i in astrocytes in vitro and in vivo. Iron ions trigger increase in [Ca2+]i through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibits astroglial Na+-K+-ATPase, which leads to elevation in cytoplasmic Na+ concentration, thus reversing Na+/Ca2+ exchanger and thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulates phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus triggering InsP3 receptor-mediated Ca2+ release from endoplasmic reticulum. In summary, these findings reveal the mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload.

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“…Our previous experiments have shown that formation of brain deposits of iron up-regulates astroglial expression of TFR and instigates reactive astrogliosis62 . What characterises the iron-induced reactive phenotype and what is the role of astroglial reactivity in managing excessive iron in the brain remains to be found.…”

mentioning

confidence: 97%

Astrocytes express DMT1 and transferrin receptors, which transport iron thus activating Ca²⁺signalling: possible role in neuroprotection against iron overload?

Xia

Guan

et al. 2020

Preprint

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ABSTRACTIron is the fundamental element for numerous physiological functions. Reduced ferrous (Fe2+) and oxidized ferric (Fe3+) are the two ionized iron states in the living organisms. In the cell membrane, divalent metal ion transporter 1 (DMT1) is responsible for cellular uptake of Fe2+, whereas transferrin receptors (TFR) carry transferrin (TF)-bound Fe3+. In this study we performed, for the first time, detailed analysis of the action of Fe ions on cytoplasmic free calcium ion concentration ([Ca2+]i) in astrocytes. Using qPCR and immunocytochemistry we identified DMT1 and TFR in astrocytes in primary cultures, in acutely isolated astrocytes and in brain tissue preparations; in situ both DMT1 and TFR are concentrated in astroglial perivascular endfeet. Administration of Fe2+ or Fe3+ in low μM concentrations evoked Ca2+ signals in astrocytes in vitro and in vivo. Iron ions triggered increase in [Ca2+]i by acting through two distinct molecular cascades. Uptake of Fe2+ by DMT1 inhibited astroglial Na+-K+-ATPase (NKA), which led to an elevation in cytoplasmic Na+ concentration (as measured by SBFI probe), thus reversing Na+/Ca2+ exchanger (NCX) thereby generating Ca2+ influx. Uptake of Fe3+ by TF-TFR stimulated phospholipase C to produce inositol 1,4,5-trisphosphate (InsP3), thus trigering InsP3 receptor-mediated Ca2+ release from the endoplasmic reticulum. Iron-induced Ca2+ signals promote astroglial release of arachidonic acid and prostaglandin E2 cytokines by activating cytosolic phospholipase A2 (cPLA2) and NF-κB signalling cascade. In summary, these findings reveal new mechanisms of iron-induced astrocytic signalling operational in conditions of iron overload, in response to which astrocytes actively accumulate excessive iron and activate neuroprotective pathways.

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Iron Aggravates the Depressive Phenotype of Stressed Mice by Compromising the Glymphatic System

Cited by 29 publications

References 14 publications

Astrocytes in heavy metal neurotoxicity and neurodegeneration

Astrocytes in heavy metal neurotoxicity and neurodegeneration

Iron induces two distinct Ca2+ signalling cascades in astrocytes

Astrocytes express DMT1 and transferrin receptors, which transport iron thus activating Ca²⁺signalling: possible role in neuroprotection against iron overload?

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Iron Aggravates the Depressive Phenotype of Stressed Mice by Compromising the Glymphatic System

Cited by 29 publications

References 14 publications

Astrocytes in heavy metal neurotoxicity and neurodegeneration

Astrocytes in heavy metal neurotoxicity and neurodegeneration

Iron induces two distinct Ca2+ signalling cascades in astrocytes

Astrocytes express DMT1 and transferrin receptors, which transport iron thus activating Ca2+signalling: possible role in neuroprotection against iron overload?

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Astrocytes express DMT1 and transferrin receptors, which transport iron thus activating Ca²⁺signalling: possible role in neuroprotection against iron overload?