A Novel Model for Brain Iron Uptake: Introducing the Concept of Regulation

Simpson, Ian A.; Ponnuru, Padmavathi; Klinger, Marianne; Myers, Roland L.; Devraj, Kavi; Coe, Christopher L.; Lubach, Gabriele R.; Carruthers, Anthony; Connor, James R.

doi:10.1038/jcbfm.2014.168

Cited by 119 publications

(202 citation statements)

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“…Paracrine factors released by glia are known to regulate the expression of iron homeostasis proteins in endothelial cells (14,15). We used a Transwell system to mimic the BBB in vitro to test the effect of iron-conditioned glial cell medium on NHE9 expression in hBMVECs (14,15,39).…”

Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

“…4B). In response to iron starvation, mammalian cells are known to decrease the levels of iron storage protein, ferritin, and increase TfR expression, ultimately resulting in iron uptake (14,45). Hence, we evaluated ferritin and TfR expression by Western blotting analysis.…”

Section: Nhe9 Expression In Hbmvecs Activates Iron Starvationmentioning

confidence: 99%

“…BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2,13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine factors released by neighboring astrocytes communicate iron status of the brain to BMVECs (14,15).…”

mentioning

confidence: 99%

“…It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine factors released by neighboring astrocytes communicate iron status of the brain to BMVECs (14,15). In vitro studies have so far identified hepcidin, ceruloplasmin, interleukin-6, soluble amyloid precursor protein, and holo-transferrin as some of the candidates in astrocyte secretome that communicate iron status to BMVECs (14 -16).…”

mentioning

confidence: 99%

“…In vitro studies have so far identified hepcidin, ceruloplasmin, interleukin-6, soluble amyloid precursor protein, and holo-transferrin as some of the candidates in astrocyte secretome that communicate iron status to BMVECs (14 -16). Secretions from astroglial cells cultured in iron-deficient and -loaded media have been shown to differentially regulate the expression and distribution of the known iron transport protein transferrin receptor in BMVECs (14). The dynamics of brain iron uptake are far from understood.…”

mentioning

confidence: 99%

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Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserIron is essential for brain function, with loss of iron homeostasis in the brain linked to neurological diseases ranging from rare syndromes to more common disorders, such as Parkinson's and Alzheimer's diseases. Iron entry into the brain is regulated by the blood-brain barrier (BBB). Molecular mechanisms regulating this transport are poorly understood. Using an in vitro model of the BBB, we identify NHE9, an endosomal cation/proton exchanger, as a novel regulator of this system. Human brain microvascular endothelial cells (hBMVECs) that constitute the BBB receive brain iron status information via paracrine signals from ensheathing astrocytes. In hBMVECs, we show that NHE9 expression is up-regulated very early in a physiological response invoked by paracrine signals from iron-starved astrocytes. Ectopic expression of NHE9 in hBMVECs without external cues induced up-regulation of the transferrin receptor (TfR) and down-regulation of ferritin, leading to an increase in iron uptake. Mechanistically, we demonstrate that NHE9 localizes to recycling endosomes in hBMVECs where it raises the endosomal pH. The ensuing alkalization of the endosomal lumen increased translocation of TfRs to the hBMVEC membrane. TfRs on the membrane were previously shown to facilitate both recycling-dependent and -independent iron uptake. We propose that NHE9 regulates TfR-dependent, recycling-independent iron uptake in hBMVECs by fine-tuning the endosomal pH in response to paracrine signals and is therefore an important regulator in iron mobilization pathway at the BBB.There is high demand for iron in the brain, one of the most metabolically active organs in the body (1, 2). Iron is a co-factor of several proteins involved in specialized brain cell functions such as synthesis of neurotransmitters and myelination (3-5). Iron is also necessary for housekeeping functions such as mitochondrial respiration and DNA synthesis, crucial for brain function (5). Insufficient or surplus iron in the brain has been associated with various neurological diseases (6 -10). Although iron deficiency is associated with cognitive and brain structural deficits, excess brain iron is implicated in Alzheimer's, Parkinson's, and other neurodegenerative diseases (10, 11). Therefore, it is not surprising that iron levels are tightly regulated in the brain (10).Iron entry into the brain is regulated by the blood-brain barrier (BBB) 3 (10). This physiological barrier is characterized by tight junctions between brain microvascular endothelial cells (BMVECs) that block passive diffusion of iron into the brain (12). BMVECs are polarized cells with one surface (apical) facing the blood and the other (basal or abluminal) facing interstitial fluid of the brain. BMVECs and ensheathing astrocytes form the regulatory axis of the BBB, modulating iron transport from blood into the brain interstitium (2, 13). It is now known that BMVECs are the focal point for regulation of cerebral iron homeostasis and not mere conduits for iron transport (14). Paracrine fac...

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Section: Nhe9 Expression Correlates With Iron Distribution In Adultmentioning

confidence: 99%

Section: Nhe9 Expression In Hbmvecs Activates Iron Starvationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Beydoun¹,

Hamood²,

Zubieta

et al. 2017

Journal of Biological Chemistry

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Graphene‐Based Materials for Brain Targeting

Aderibigbe

Naki

Owonubi

2019

Handbook of Graphene

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Cell‐Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP

Lee

Martínez-Valbuena

Andrea

et al. 2022

Annals of Neurology

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Objective Progressive supranuclear palsy (PSP) is a 4R‐tauopathy showing heterogeneous tau cytopathology commencing in the globus pallidus (GP) and the substantia nigra (SN), regions also associated with age‐related iron accumulation. Abnormal iron levels have been extensively associated with tau pathology in neurodegenerative brains, however, its role in PSP pathogenesis remains yet unknown. We perform the first cell type‐specific evaluation of PSP iron homeostasis and the closely related oxygen homeostasis, in relation to tau pathology in human postmortem PSP brains. Methods In brain regions vulnerable to PSP pathology (GP, SN, and putamen), we visualized iron deposition in tau‐affected and unaffected neurons, astroglia, oligodendrocytes, and microglia, using a combination of iron staining with immunolabelling. To further explore molecular pathways underlying our observations, we examined the expression of key iron and oxygen homeostasis mRNA transcripts and proteins. Results We found astrocytes as the major cell type accumulating iron in the early affected regions of PSP, highly associated with cellular tau pathology. The same regions are affected by dysregulated expression of alpha and beta hemoglobin and neuroglobin showing contrasting patterns. We discovered changes in iron and oxygen homeostasis‐related gene expression associated with aging of the brain, and identified dysregulated expression of rare neurodegeneration with brain iron accumulation (NBIA) genes associated with tau pathology to distinguish PSP from the healthy aging brain. Interpretation We present novel aspects of PSP pathophysiology highlighting an overlap with NBIA pathways. Our findings reveal potential novel targets for therapy development and have implications beyond PSP for other iron‐associated neurodegenerative diseases. ANN NEUROL 2023;93:431–445

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A Novel Model for Brain Iron Uptake: Introducing the Concept of Regulation

Cited by 119 publications

References 43 publications

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation

Graphene‐Based Materials for Brain Targeting

Cell‐Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP

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