DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration

Ingrassia, Rosaria; Garavaglia, Barbara; Memo, Maurizio

doi:10.3389/fnins.2019.00575

Cited by 37 publications

(30 citation statements)

References 118 publications

(169 reference statements)

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“…Iron metabolism is tightly regulated through a number of mechanisms and proteins. The upregulation of iron importer DMT-1 and downregulation of iron exporter ferroportin1 is a consequence of inflammatory stimuli and vice versa ( 26 , 27 ). Transferrin is able to buffer iron ( 28 ) but can also be rapidly effluxed from the brain to the blood ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis

et al. 2021

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ObjectiveProgressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine in vitro and in chronic experimental autoimmune encephalomyelitis (EAE).MethodsMicroglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry.ResultsIron impaired microglial function in vitro regarding phagocytosis and markers of inflammation; this was regulated by clozapine, reflected in reduced release of IL-6 and normalization of neuronal phagocytosis. In chronic EAE, clozapine dose-dependently attenuated clinical signs and still had an effect if applied in a therapeutic setting. Early mild sedative effects habituated over time. Histologically, demyelination was reduced by clozapine and positive effects on inflammation strongly correlated with reduced iron deposition. This was accompanied by reduced expression of DMT-1, an iron transport protein.ConclusionsClozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS.

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Section: Discussionmentioning

confidence: 99%

Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis

et al. 2021

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“…The effects of DIO on DMT1 gene expression reported in the literature have focused primarily on male rodents and the system, leaving a knowledge gap on DIO impact in the brain and the effect of sex on potential gene expression alterations. More investigations are needed to learn about the gene expression of DMT1 in the brain under DIO conditions, as the dysregulation of DMT1 and trace element homeostasis is associated with various neurodegenerative diseases [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Diet-Induced Obesity Disrupts Trace Element Homeostasis and Gene Expression in the Olfactory Bulb

2020

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The aim of this study was to determine the impact of diet-induced obesity (DIO) on trace element homeostasis and gene expression in the olfactory bulb and to identify potential interaction effects between diet, sex, and strain. Our study is based on evidence that obesity and olfactory bulb impairments are linked to neurodegenerative processes. Briefly, C57BL/6J (B6J) and DBA/2J (D2J) male and female mice were fed either a low-fat diet or a high-fat diet for 16 weeks. Brain tissue was then evaluated for iron, manganese, copper, and zinc concentrations and mRNA gene expression. There was a statistically significant diet-by-sex interaction for iron and a three-way interaction between diet, sex, and strain for zinc in the olfactory bulb. Obese male B6J mice had a striking 75% increase in iron and a 50% increase in manganese compared with the control. There was an increase in zinc due to DIO in B6J males and D2J females, but a decrease in zinc in B6J females and D2J males. Obese male D2J mice had significantly upregulated mRNA gene expression for divalent metal transporter 1, alpha-synuclein, amyloid precursor protein, dopamine receptor D2, and tyrosine hydroxylase. B6J females with DIO had significantly upregulated brain-derived neurotrophic factor expression. Our results demonstrate that DIO has the potential to disrupt trace element homeostasis and mRNA gene expression in the olfactory bulb, with effects that depend on sex and genetics. We found that DIO led to alterations in iron and manganese predominantly in male B6J mice, and gene expression dysregulation mainly in male D2J mice. These results have important implications for health outcomes related to obesity with possible connections to neurodegenerative disease.

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“…The DMT1, another important iron-absorbing protein, is also closely associated with brain iron accumulation in neurodegenerative diseases. Multiple studies have shown that DMT1 overexpression contributed to iron accumulation in the substantia nigra and dopaminergic neuron loss (Salazar et al, 2008;Zhang et al, 2017;Ingrassia et al, 2019). Ferritin is the main intracellular iron storage protein composed of FTL1 (light chains) and FTH1 (ferritin heavy), which preserves excess iron in a redox inactive form and prevents the cell and tissue from oxidative damage (Theil, 2013;Dowdle et al, 2014;Lal, 2019).…”

Section: Ferroptosis and Ironmentioning

confidence: 99%

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

2020

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Iron is an essential transition metal for numerous biologic processes in mammals. Iron metabolism is regulated via several coordination mechanisms including absorption, utilization, recycling, and storage. Iron dyshomeostasis can result in intracellular iron retention, thereby damaging cells, tissues, and organs through free oxygen radical generation. Numerous studies have shown that brain iron overload is involved in the pathological mechanism of neurodegenerative disease including Alzheimer's disease (AD). However, the underlying mechanisms have not been fully elucidated. Ferroptosis, a newly defined iron-dependent form of cell death, which is distinct from apoptosis, necrosis, autophagy, and other forms of cell death, may provide us a new viewpoint. Here, we set out to summarize the current knowledge of iron metabolism and ferroptosis, and review the contributions of iron and ferroptosis to AD.

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DMT1 Expression and Iron Levels at the Crossroads Between Aging and Neurodegeneration

Cited by 37 publications

References 118 publications

Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis

Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis

Diet-Induced Obesity Disrupts Trace Element Homeostasis and Gene Expression in the Olfactory Bulb

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

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