Metallothionein Treatment Attenuates Microglial Activation and Expression of Neurotoxic Quinolinic Acid Following Traumatic Brain Injury

Chung, Roger S.; Leung, Y. K.; Butler, Chris W.; Chen, Yingjun; Eaton, Emma D.; Pankhurst, Michael W.; West, Adrian K.; Guillemin, Gilles J.

doi:10.1007/s12640-009-9044-y

Cited by 28 publications

(25 citation statements)

References 34 publications

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“…Moreover, the results are generally consistent with those found in Mt1&2 KO mice [12]. An inhibitory effect of MT-1/2 on microglia has also been suggested in other studies [25,26,27]. Altogether, the present results suggest that while MT-1 may have a direct inhibitory role controlling microglia, it is overridden by an indirect stimulatory role in the case of APP positive mice because of its effects on the formation of amyloid plaques.…”

Section: Discussionsupporting

confidence: 89%

Influence of Transgenic Metallothionein-1 on Gliosis, CA1 Neuronal Loss, and Brain Metal Levels of the Tg2576 Mouse Model of Alzheimer’s Disease

Comes

Manso

Escrig

et al. 2017

IJMS

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The mouse model of Alzheimer’s disease (AD), Tg2576 mice (APP), has provided valuable information, such as the role of the metallothionein (MT) family in their behavioral and amyloidosis phenotypes. In this study, we further characterize the role of MT-1 by crossing Mt1-overexpressing mice with Tg2576 mice (APPTgMT). In 14-month-old mice, MT-1(/2) protein levels were dramatically increased by Mt1 overexpression throughout the cortex (Cx), which showed a prominent caudal-rostral gradient, and the hippocampus (HC). There was a trend for MT-1(/2) immunostaining to be increased in the areas surrounding the amyloid plaques in control male mice but not in Mt1-overexpressing mice. Gliosis was elicited by the amyloid plaques, but the effects of Mt1 overexpression were modest. However, in hippocampal western blots the microglial marker Iba-1 was increased in old male APPTgMT mice compared to APP-wild type (APPWT) mice, and the opposite was observed in young mice. Hippocampal CA1 neuronal loss was observed in Tg2576 mice, but was unaffected by Mt1 overexpression. Aging increased Zn and Cu levels differently depending on brain area, sex, and genotype. Thus, the effects of Mt1 overexpression on the phenotype of Tg2576 mice here studied are modest.

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Section: Discussionsupporting

confidence: 89%

Influence of Transgenic Metallothionein-1 on Gliosis, CA1 Neuronal Loss, and Brain Metal Levels of the Tg2576 Mouse Model of Alzheimer’s Disease

Comes

Manso

Escrig

et al. 2017

IJMS

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“…Neuroinflammation has been linked to alpha-synucleinopathies and there is evidence of a role of MTs in inflammation in brain injury (Chung et al, 2009; Pedersen et al, 2009; Shastri et al, 2013; Vieira et al, 2015). MTs have been implicated in inflammatory states and act as exchangeable zinc stores which can swap with toxic metals, such as copper and cadmium (Rofe et al, 1992; Meloni et al, 2008).…”

Section: Oxidative Stress and Neuroinflammationmentioning

confidence: 99%

“…Astrocytes, the primary cell type expressing MT-1/2 in the brain, up-regulate MT-1/2 expression as a physiological response which may promote neuroregeneration as well as survival (Chung et al, 2008; Landowski et al, 2016). Treatment with MT-2 attenuated the immune response of neurotoxic quinolinic acid production in brain injury (Chung et al, 2009). More recently, overexpression of MT-1 in a mouse model of AD promoted reversal in behavioral symptoms of disease and more inert soluble amyloid species (Manso et al, 2016).…”

Section: Oxidative Stress and Neuroinflammationmentioning

confidence: 99%

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

et al. 2017

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Metallothioneins (MTs) are proteins that function by metal exchange to regulate the bioavailability of metals, such as zinc and copper. Copper functions in the brain to regulate mitochondria, neurotransmitter production, and cell signaling. Inappropriate copper binding can result in loss of protein function and Cu(I)/(II) redox cycling can generate reactive oxygen species. Copper accumulates in the brain with aging and has been shown to bind alpha-synuclein and initiate its aggregation, the primary aetiological factor in Parkinson's disease (PD), and other alpha-synucleinopathies. In PD, total tissue copper is decreased, including neuromelanin-bound copper and there is a reduction in copper transporter CTR-1. Conversely cerebrospinal fluid (CSF) copper is increased. MT-1/2 expression is increased in activated astrocytes in alpha-synucleinopathies, yet expression of the neuronal MT-3 isoform may be reduced. MTs have been implicated in inflammatory states to perform one-way exchange of copper, releasing free zinc and recent studies have found copper bound to alpha-synuclein is transferred to the MT-3 isoform in vitro and MT-3 is found bound to pathological alpha-synuclein aggregates in the alpha-synucleinopathy, multiple systems atrophy. Moreover, both MT and alpha-synuclein can be released and taken up by neural cells via specific receptors and so may interact both intra- and extra-cellularly. Here, we critically review the role of MTs in copper dyshomeostasis and alpha-synuclein aggregation, and their potential as biomarkers and therapeutic targets.

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“…Similarly, extracellular MT reduces the inflammatory response of microglia following activation (Chung et al 2009). These findings complement earlier work by Lynes’ group, which showed that MT was able to act in a chemokine-like manner and to influence the migration of leukocytes (Yin et al 2005).…”

Section: Endogenous Neuroprotective Molecules (Akw Gjg)mentioning

confidence: 99%

New Strategies in Neuroprotection and Neurorepair

et al. 2011

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There are currently few clinical strategies in place, which provide effective neuroprotection and repair, despite an intense international effort over the past decades. One possible explanation for this is that a deeper understanding is required of how endogenous mechanisms act to confer neuroprotection. This mini-review reports the proceedings of a recent workshop “Neuroprotection and Neurorepair: New Strategies” (Iguazu Falls, Misiones, Argentina, April 11–13, 2011, Satellite Symposium of the V Neurotoxicity Society Meeting, 2011) in which four areas of active research were identified to have the potential to generate new insights into this field. Topics discussed were i) metallothionein and other multipotent neuroprotective molecules; ii) oxidative stress and their signal mediated pathways in neuroregeneration; iii) neurotoxins in glial cells, and iv) drugs of abuse with neuroprotective effects.

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Metallothionein Treatment Attenuates Microglial Activation and Expression of Neurotoxic Quinolinic Acid Following Traumatic Brain Injury

Cited by 28 publications

References 34 publications

Influence of Transgenic Metallothionein-1 on Gliosis, CA1 Neuronal Loss, and Brain Metal Levels of the Tg2576 Mouse Model of Alzheimer’s Disease

Influence of Transgenic Metallothionein-1 on Gliosis, CA1 Neuronal Loss, and Brain Metal Levels of the Tg2576 Mouse Model of Alzheimer’s Disease

Metallothionein, Copper and Alpha-Synuclein in Alpha-Synucleinopathies

New Strategies in Neuroprotection and Neurorepair

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