In vivo evaluation of microglia activation by intracranial iron overload in central pain after spinal cord injury

Meng, Fan Xing; Hou, Jing Ming; Sun, Chuiguo

doi:10.1186/s13018-017-0578-z

Cited by 26 publications

(15 citation statements)

References 54 publications

(51 reference statements)

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“…Therefore, a possibility exists that increasing iron storage experimentally would induce the changes observed in dystrophic microglia in vivo. There is already considerable evidence that iron-overload can induce senescent changes in cells including microglia [ 56 , 57 , 58 ]. In this light, our finding that cultured microglia maintained in a high iron environment adopt characteristics of dystrophic microglia is not surprising.…”

Section: Discussionmentioning

confidence: 99%

Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity

Angelova

Brown

2018

Biomolecules

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Aging is the most prominent risk factor for most neurodegenerative diseases. However, incorporating aging-related changes into models of neurodegeneration rarely occurs. One of the significant changes that occurs in the brain as we age is the shift in phenotype of the resident microglia population to one less able to respond to deleterious changes in the brain. These microglia are termed dystrophic microglia. In order to better model neurodegenerative diseases, we have developed a method to convert microglia into a senescent phenotype in vitro. Mouse microglia grown in high iron concentrations showed many characteristics of dystrophic microglia including, increased iron storage, increased expression of proteins, such as ferritin and the potassium channel, Kv1.3, increased reactive oxygen species production and cytokine release. We have applied this new model to the study of α-synuclein, a protein that is closely associated with a number of neurodegenerative diseases. We have shown that conditioned medium from our model dystrophic microglia increases α-synuclein transcription and expression via tumor necrosis factor alpha (TNFα) and mediated through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The conditioned medium also decreases the formation of α-synuclein tetramers, associated ferrireductase activity, and increases aggregates of α-synuclein. The results suggest that we have developed an interesting new model of aged microglia and that factors, including TNFα released from dystrophic microglia could have a significant influence on the pathogenesis of α-synuclein related diseases.

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Section: Discussionmentioning

confidence: 99%

Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity

Angelova

Brown

2018

Biomolecules

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“…This is particularly interesting since traumatic brain injury is a potential risk factor for AD [3] . Excess iron has also been shown to activate microglia by inducing the nuclear factor-κB (NF-κB)-mediated transcription of proinflammatory cytokines [75,76] . Interestingly, the accumulation of inflammatory signals, such as TNF-α and IL-6, triggers the upregulation of DMT1 and downregulation of ferroportin, suggesting that the mechanism for iron accumulation into neurons and microglia during inflammation is in part due to changes in the levels of iron transporters [77] .…”

Section: Iron (Fe)mentioning

confidence: 99%

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

Huat

Camats-Perna

Newcombe

et al. 2019

Journal of Molecular Biology

341

180

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As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socioeconomic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.

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“…Microglial are highly reactive cells responding to increased iron levels in the brain. When iron level increases in brain, microglia become activated ( Meng et al, 2017 ), with soma volume increased and process length decreased ( Rathnasamy et al, 2013 ; Donley et al, 2021 ). Iron may activate microglia through proinflammatory cytokines mediated by the nuclear factor-κB (NF-κB) ( Meng et al, 2017 ).…”

Section: Impact Of Iron Overload On Alzheimer’s Disease Pathologymentioning

confidence: 99%

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

Wang

Shen

et al. 2022

Front. Aging Neurosci.

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Iron plays a crucial role in many physiological processes of the human body, but iron is continuously deposited in the brain as we age. Early studies found iron overload is directly proportional to cognitive decline in Alzheimer’s disease (AD). Amyloid precursor protein (APP) and tau protein, both of which are related to the AD pathogenesis, are associated with brain iron metabolism. A variety of iron metabolism-related proteins have been found to be abnormally expressed in the brains of AD patients and mouse models, resulting in iron deposition and promoting AD progression. Amyloid β (Aβ) and hyperphosphorylated tau, two pathological hallmarks of AD, can also promote iron deposition in the brain, forming a vicious cycle of AD development-iron deposition. Iron deposition and the subsequent ferroptosis has been found to be a potential mechanism underlying neuronal loss in many neurodegenerative diseases. Iron chelators, antioxidants and hepcidin were found useful for treating AD, which represents an important direction for AD treatment research and drug development in the future. The review explored the deep connection between iron dysregulation and AD pathogenesis, discussed the potential of new hypothesis related to iron dyshomeostasis and ferroptosis, and summarized the therapeutics capable of targeting iron, with the expectation to draw more attention of iron dysregulation and corresponding drug development.

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In vivo evaluation of microglia activation by intracranial iron overload in central pain after spinal cord injury

Cited by 26 publications

References 54 publications

Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity

Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity

Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation

Iron Dyshomeostasis and Ferroptosis: A New Alzheimer’s Disease Hypothesis?

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