Ceruloplasmin deletion in myelinating glial cells induces myelin disruption and oxidative stress in the central and peripheral nervous systems

González, Diara A. Santiago; Cheli, Verónica T.; Rosenblum, Shaina L.; Denaroso, Giancarlo; Paez, Pablo M.

doi:10.1016/j.redox.2021.102118

Cited by 10 publications

(12 citation statements)

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“…The formation of learning and memory requires a complete synaptic framework and active circuit plasticity [ 38 ]; learning and forgetting are associated with synaptic formation and elimination on axonal-dendritic overlaps [ 39 ]. Recent studies have shown that conditional knockout of Cp in oligodendrocytes induces iron overload, brain oxidative stress, myelin disruption and neurodegeneration in aged mice [ 40 ]. In our study, we examined the expression of SYN and PSD95, as well as synaptic structure.…”

Section: Discussionmentioning

confidence: 99%

“…Based on our working model in which astrocytic CP is required for iron translocation across the BBB, the deletion of Cp is expected to limit the amount of iron in the brain, which is contrary to the results of iron deposition in the brain of global Cp knockout mice [ 3 , 11 , 12 , 40 ]. In order to exclude whether peripheral CP and iron levels have an effect on the decrease of brain iron in Cp Gfap cKO mice, we examined the CP protein levels and iron contents in the liver and blood in the Cp Gfap cKO mice and controls (Fig S 7 ).…”

Section: Discussionmentioning

confidence: 99%

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The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice

Kang

et al. 2022

Cell Death Dis

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Ceruloplasmin (CP) plays an important role in maintaining iron homeostasis. Cp gene knockout (Cp-/-) mice develop a neurodegenerative disease with aging and show iron accumulation in the brain. However, iron deficiency has also been observed in 3 M Cp-/- mice. The use of systemic Cp gene knockout is insufficient to reveal specific functions for CP in the central nervous system. Considering recent discoveries that astrocytes synthetize the majority of brain CP, we generated astrocyte conditional Cp knockout (CpGfapcKO) mice, and found that iron contents decreased in the cerebral cortex and hippocampus of young (6 M) and old (18 M) CpGfapcKO mice. Further experiments revealed that 6 M CpGfapcKO mice exhibited impaired learning and memory function, while 18 M CpGfapcKO mice exhibited improved learning and memory function. Our study demonstrates that astrocytic Cp deletion blocks brain iron influx through the blood-brain-barrier, with concomitantly increased iron levels in brain microvascular endothelial cells, resulting in brain iron deficiency and down-regulation of ferritin levels in neurons, astrocytes, microglia and oligodendrocytes. At the young age, the synapse density, synapse-related protein levels, 5-hydroxytryptamine and norepinephrine, hippocampal neurogenesis and myelin formation were all decreased in CpGfapcKO mice. These changes affected learning and memory impairment in young CpGfapcKO mice. In old CpGfapcKO mice, iron accumulation with aging was attenuated, and was accompanied by the alleviation of the ROS-MAPK-apoptosis pathway, Tau phosphorylation and β-amyloid aggregation, thus delaying age-related memory decline. Overall, our results demonstrate that astrocytic Cp deletion has divergent effects on learning and memory function via different regulatory mechanisms induced by decreased iron contents in the brain of mice, which may present strategies for the prevention and treatment of dementia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice

Kang

et al. 2022

Cell Death Dis

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“…Cp expression in myelinating glial cells is crucial to prevent oxidative stress and neurodegeneration in the central and peripheral nervous systems [ 61 ]. Lower plasma Cp levels may contribute to ASD pathophysiology in young individuals [ 62 , 63 , 64 ]. AA is a known regulator of signal transduction proteins and acts as a precursor of potent signaling molecules [ 63 , 64 , 65 ].…”

Section: Copper Signalingmentioning

confidence: 99%

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder

Yui

Imataka

Yoshihara

2022

IJMS

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The signaling pathways associated with lipid metabolism contribute to the pathophysiology of autism spectrum disorder (ASD) and provide insights for devising new therapeutic strategies. Prostaglandin E2 is a membrane-derived lipid molecule that contributes to developing ASD associated with canonical Wnt signaling. Cyclooxygenase-2 plays a key role in neuroinflammation and is implicated in the pathogenesis of neurodevelopmental diseases, such as ASD. The endocannabinoid system maintains a balance between inflammatory and redox status and synaptic plasticity and is a potential target for ASD pathophysiology. Redox signaling refers to specific and usually reversible oxidation–reduction reactions, some of which are also involved in pathways accounting for the abnormal behavior observed in ASD. Redox signaling and redox status-sensitive transcription factors contribute to the pathophysiology of ASD. Cannabinoids regulate the redox balance by altering the levels and activity of antioxidant molecules via ROS-producing NADPH oxidase (NOX) and ROS-scavenging superoxide dismutase enzymes. These signaling cascades integrate a broad range of neurodevelopmental processes that may be involved in the pathophysiology of ASD. Based on these pathways, we highlight putative targets that may be used for devising novel therapeutic interventions for ASD.

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“…These abnormalities were combined with reductions in the thickness of the somatosensory cortex and elevated levels of iron depositions, oxidative stress, and apoptotic cell death in cortical neurons. Toxic ferrous iron released by Cp deficient astrocytes can produce free radical formation in neurons and activate a sequence of pathological events causing axonal degeneration and apoptotic cell death (Chen et al, 2019; Santiago González et al, 2021). Additionally, oligodendrocyte iron overload and demyelination might inactivate mechanisms in these cells that provide antioxidant protection and metabolic support to neurons (Mukherjee et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain

Cheli

Sekhar

González

et al. 2023

Glia

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Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux. The absence of this protein in humans and rodents produces progressive neurodegeneration with brain iron accumulation. Astrocytes express high levels of Cp and iron efflux from these cells has been shown to be central for oligodendrocyte maturation and myelination. To explore the role of astrocytic Cp in brain development and aging we generated a specific conditional KO mouse for Cp in astrocytes (Cp cKO). Deletion of Cp in astrocytes during the first postnatal week induced hypomyelination and a significant delay in oligodendrocyte maturation. This abnormal myelin synthesis was exacerbated throughout the first two postnatal months and accompanied by a reduction in oligodendrocyte iron content, as well as an increase in brain oxidative stress.In contrast to young animals, deletion of astrocytic Cp at 8 months of age engendered iron accumulation in several brain areas and neurodegeneration in cortical regions. Aged Cp cKO mice also showed myelin loss and oxidative stress in oligodendrocytes and neurons, and at 18 months of age, developed abnormal behavioral profiles, including deficits in locomotion and short-term memory. In summary, our results demonstrate that iron efflux-mediated by astrocytic Cp-is essential for both early oligodendrocyte maturation and myelin integrity in the mature brain. Additionally, our data suggest that astrocytic Cp activity is central to prevent iron accumulation and iron-induced oxidative stress in the aging CNS.

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Ceruloplasmin deletion in myelinating glial cells induces myelin disruption and oxidative stress in the central and peripheral nervous systems

Cited by 10 publications

References 43 publications

The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice

The divergent effects of astrocyte ceruloplasmin on learning and memory function in young and old mice

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder

The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain

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