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Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention

The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic aqueous chemistry of this first-row transitio...

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Autores principales: Rosenblum, Shaina L., Kosman, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964494/
https://www.ncbi.nlm.nih.gov/pubmed/35370907
http://dx.doi.org/10.3389/fneur.2022.855751
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author Rosenblum, Shaina L.
Kosman, Daniel J.
author_facet Rosenblum, Shaina L.
Kosman, Daniel J.
author_sort Rosenblum, Shaina L.
collection PubMed
description The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic aqueous chemistry of this first-row transition metal. Although a mechanistic understanding of the link between brain iron accumulation (BIA) and neurodegenerative diseases is lacking, BIA is co-morbid with the majority of cognitive and motor function disorders. The most prevalent neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple System Atrophy (MSA), and Multiple Sclerosis (MS), often present with increased deposition of iron into the brain. In addition, ataxias that are linked to mutations in mitochondrial-localized proteins (Friedreich's Ataxia, Spinocerebellar Ataxias) result in mitochondrial iron accumulation and degradation of proton-coupled ATP production leading to neuronal degeneration. A comorbidity common in the elderly is a chronic systemic inflammation mediated by primary cytokines released by macrophages, and acute phase proteins (APPs) released subsequently from the liver. Abluminal inflammation in the brain is found downstream as a result of activation of astrocytes and microglia. Reasonably, the iron that accumulates in the brain comes from the cerebral vasculature via the microvascular capillary endothelial cells whose tight junctions represent the blood-brain barrier. A premise amenable to experimental interrogation is that inflammatory stress alters both the trans- and para-cellular flux of iron at this barrier resulting in a net accumulation of abluminal iron over time. This review will summarize the evidence that lends support to this premise; indicate the mechanisms that merit delineation; and highlight possible therapeutic interventions based on this model.
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spelling pubmed-89644942022-03-31 Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention Rosenblum, Shaina L. Kosman, Daniel J. Front Neurol Neurology The redox properties that make iron an essential nutrient also make iron an efficient pro-oxidant. Given this nascent cytotoxicity, iron homeostasis relies on a combination of iron transporters, chaperones, and redox buffers to manage the non-physiologic aqueous chemistry of this first-row transition metal. Although a mechanistic understanding of the link between brain iron accumulation (BIA) and neurodegenerative diseases is lacking, BIA is co-morbid with the majority of cognitive and motor function disorders. The most prevalent neurodegenerative disorders, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple System Atrophy (MSA), and Multiple Sclerosis (MS), often present with increased deposition of iron into the brain. In addition, ataxias that are linked to mutations in mitochondrial-localized proteins (Friedreich's Ataxia, Spinocerebellar Ataxias) result in mitochondrial iron accumulation and degradation of proton-coupled ATP production leading to neuronal degeneration. A comorbidity common in the elderly is a chronic systemic inflammation mediated by primary cytokines released by macrophages, and acute phase proteins (APPs) released subsequently from the liver. Abluminal inflammation in the brain is found downstream as a result of activation of astrocytes and microglia. Reasonably, the iron that accumulates in the brain comes from the cerebral vasculature via the microvascular capillary endothelial cells whose tight junctions represent the blood-brain barrier. A premise amenable to experimental interrogation is that inflammatory stress alters both the trans- and para-cellular flux of iron at this barrier resulting in a net accumulation of abluminal iron over time. This review will summarize the evidence that lends support to this premise; indicate the mechanisms that merit delineation; and highlight possible therapeutic interventions based on this model. Frontiers Media S.A. 2022-03-15 /pmc/articles/PMC8964494/ /pubmed/35370907 http://dx.doi.org/10.3389/fneur.2022.855751 Text en Copyright © 2022 Rosenblum and Kosman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Rosenblum, Shaina L.
Kosman, Daniel J.
Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
title Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
title_full Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
title_fullStr Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
title_full_unstemmed Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
title_short Aberrant Cerebral Iron Trafficking Co-morbid With Chronic Inflammation: Molecular Mechanisms and Pharmacologic Intervention
title_sort aberrant cerebral iron trafficking co-morbid with chronic inflammation: molecular mechanisms and pharmacologic intervention
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964494/
https://www.ncbi.nlm.nih.gov/pubmed/35370907
http://dx.doi.org/10.3389/fneur.2022.855751
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