Impact of high iron intake on cognition and neurodegeneration in humans and in animal models: a systematic review

Agrawal, Shweta; Berggren, Kiersten L.; Marks, Eileen; Fox, Jonathan H.

doi:10.1093/nutrit/nux015

Cited by 46 publications

(60 citation statements)

References 88 publications

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“…Particularly in populations living at HA this may expose to iron overload. Recently, a systematic review provided preclinical evidence of adverse effect of high iron intake in neonates on brain-health-related outcomes in adults [12]. …”

Section: To the Editormentioning

confidence: 99%

Correcting the cut‐off point of hemoglobin at high altitude favors misclassification of anemia, erythrocytosis and excessive erythrocytosis

et al. 2017

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Section: To the Editormentioning

confidence: 99%

Correcting the cut‐off point of hemoglobin at high altitude favors misclassification of anemia, erythrocytosis and excessive erythrocytosis

et al. 2017

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“…To determine a possible role for iron in microglial activation, we used the NIS model. This is relevant to understanding the mechanisms through which iron promotes HD and other disorders because the doses approximate what a human infant may receive and there is no detectable short--term toxicity (Agrawal et al, 2017). We have previously reported that NIS potentiates HD in the R6/2 and YAC128 mouse models (Berggren et al, 2015, Berggren et al, 2016.…”

Section: Neonatal Iron Supplementation Activates Microglial Cellsmentioning

confidence: 99%

“…This model is relevant, as in most populations human infants are supplemented with iron to prevent deficiency. Recommended daily allowances for iron have been developed to prevent iron deficiency, and upper limits were established to avoid short--term adverse effects (Micronutrients, 2001); however, long--term consequences of iron supplementation are not understood (Agrawal et al, 2017). We have previously shown that NIS in R6/2 and YAC128 mouse models of HD exacerbates disease progression (Berggren et al, 2015, Berggren et al, 2016.…”

Section: Introductionmentioning

confidence: 99%

Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

Donley

Realing

Gigley

et al. 2019

Preprint

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Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant CAG--repeat expansion in the huntingtin gene. Morphologic activation of microglia is a key marker of neuroinflammation that is present before clinical onset in HD patients. The kynurenine pathway of tryptophan degradation is restricted in part to microglia and is activated in HD, where it contributes to disease progression. Indoleamine--2,3--dioxygenase (IDO) is a microglial enzyme that catalyzes the first step in this pathway. HD brain microglial cells also accumulate iron; however, the role of iron in promoting microglial activation and the kynurenine pathway is unclear. Based on analyses of morphological characteristics of microglia, we showed that HD mice demonstrate an activated microglial morphology compared with controls. Neonatal iron supplementation resulted in additional microglial morphology changes compared with HD controls. Increased microglial activation in iron--supplemented HD mice was indicated by increased soma volume and decreased process length. In our assessment of whether iron can affect the kynurenine pathway, iron directly enhanced the activity of human recombinant IDO1 with an EC 50 of 1.24 nM. We also detected elevated microglial cytoplasmic labile iron in N171--82Q HD mice, an increase that is consistent with the cellular location of IDO. We further demonstrated that neonatal iron supplementation, a model for studying the role of iron in neurodegeneration, activates IDO directly in the mouse brain and promotes neurodegeneration in HD mice. Kynurenine pathway metabolites were also modified in HD and by iron supplementation in wild-type mice. These findings indicate that iron dysregulation contributes to the activation of microglia and the kynurenine pathway in a mouse model of HD.

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“…Particularmente, en poblaciones que viven en la altura estas medidas bien intencionadas pueden exponer a una sobrecarga de hierro, que podría ser más bien perjudicial para la salud. Recientemente, una revisión sistemática da evidencia preclínica de efectos adversos que tiene en la salud cerebral en adultos la ingesta elevada de hierro en neonatos (51) .…”

Section: Reflexiones Finalesunclassified

Necesidades de investigación para el diagnóstico de anemia en poblaciones de altura

Gonzáles

Fano

2017

Rev Peru Med Exp Salud Publica

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RESUMENTanto la deficiencia como la sobrecarga de hierro son situaciones que ponen en riesgo la salud y la vida de las personas, por lo que es importante mantener su homeostasis. Como la hemoglobina contiene 70% del hierro del organismo, la OMS recomienda su medición para determinar la prevalencia de anemia por deficiencia de hierro (ID), a pesar que ellos mismos reconocen que la anemia no es específica de ID. Como la hemoglobina aumenta con la altitud de residencia, la OMS recomienda corregir el punto de corte para definir anemia en la altura. Una objeción a esta corrección es que el aumento de la hemoglobina en la altura no es universal ni aumenta de manera lineal. Además, las poblaciones de mayor antigüedad generacional tienen menos hemoglobina que las más recientes. En infantes, niños, gestantes y adultos, la prevalencia de anemia usando hemoglobina corregida es 3-5 veces mayor que usando marcadores del estatus de hierro. Los programas estatales buscan combatir la anemia mediante la suplementación de hierro; no obstante, resultan ineficaces, especialmente en las poblaciones de altura. Entonces, ¿hay deficiencia de hierro en la altura? Los niveles de hepcidina sérica, hormona que regula la disponibilidad de hierro, son similares a los de nivel del mar indicando que en la altura no hay deficiencia de hierro. Un problema adicional al corregir la hemoglobina por la altura, es que las prevalencias de eritrocitosis disminuyen. En conclusión, la corrección del punto de corte de la hemoglobina en la altura para determinar deficiencia de hierro es inadecuada. Palabras clave: Anemia, Deficiencia de hierro, Factor de corrección, Ferritinas (fuente: DeCS BIREME). DIAGNOSIS OF ANEMIA IN POPULATIONS AT HIGH ALTITUDES ABSTRACTIron deficiency and overload are risk factors for numerous poor health outcomes, and thus the maintenance of iron homeostasis is vital. Considering that hemoglobin contains 70% of the total iron in the body, the World Health Organization (WHO) recommends the measurement of iron levels to calculate the rate of iron deficiency anemia (IDA), although WHO recognizes that IDA is not the only cause of anemia. As hemoglobin increases with altitude, WHO recommends correcting the cut-off point to define anemia at high altitudes. An objection to this correction is that the increase in hemoglobin at high altitudes is not universal and is not linear. In addition, individuals in older age groups have lower hemoglobin levels than those in younger age groups. In infants, children, pregnant women, and adults, the prevalence of anemia using corrected hemoglobin is 3-5 times higher than that using markers of iron status. State programs seek to control anemia by means of iron supplementation. However, these programs are ineffective, particularly for high-altitude populations. Therefore, the occurrence of iron deficiency at high altitudes is controversial. The serum levels of the hormone hepcidin, which regulates iron availability, are similar in individuals at high altitudes to those of individuals at sea level, indicat...

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Impact of high iron intake on cognition and neurodegeneration in humans and in animal models: a systematic review

Cited by 46 publications

References 88 publications

Correcting the cut‐off point of hemoglobin at high altitude favors misclassification of anemia, erythrocytosis and excessive erythrocytosis

Correcting the cut‐off point of hemoglobin at high altitude favors misclassification of anemia, erythrocytosis and excessive erythrocytosis

Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington’s disease

Necesidades de investigación para el diagnóstico de anemia en poblaciones de altura

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