Chronic Exposure to High Levels of Zinc or Copper has Little Effect on Brain Metal Homeostasis or Aβ Accumulation in Transgenic APP-C100 Mice

Maynard, Christa J.; Cappai, Roberto; Volitakis, Irene; Laughton, Katrina; Masters, Colin L.; Bush, Ashley I.; Li, Qiao‐Xin

doi:10.1007/s10571-009-9401-7

Cited by 18 publications

(12 citation statements)

References 47 publications

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“…Mice fed high dietary zinc showed significantly increased zinc level in serum and hemocytes, but the total brain zinc level was not changed. This result is consistent with previous research in which BL6/DBA mice were fed high zinc diets (300–1000 ppm) for 7–17 months, the brain zinc only showed a trend but no significant elevation [38]. Another study performed by Wang et al showed a significant increase of brain zinc in transgenic APP/PS1 mice fed a high zinc diet [31], but the dosage of supplemented zinc was extremely high (ZnSO4·7H2O 20 mg/ml in drink water, which equals to about 4530 ppm Zn), which may not occur in human.…”

Section: Discussionsupporting

confidence: 93%

High Dose Zinc Supplementation Induces Hippocampal Zinc Deficiency and Memory Impairment with Inhibition of BDNF Signaling

et al. 2013

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Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.

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Section: Discussionsupporting

confidence: 93%

High Dose Zinc Supplementation Induces Hippocampal Zinc Deficiency and Memory Impairment with Inhibition of BDNF Signaling

et al. 2013

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“…28, 29 In the context of AD, however, studies on Zn 2+ deficiency or supplementation in AD models have provided conflicting results. 14, 15, 30 Here, we show that dietary Zn 2+ supplementation prevents hippocampal-dependent cognitive deficits, reduces both intraneuronal A β and tau pathology, prevents mitochondrial deficits and restores BDNF levels in a mouse model of AD.…”

Section: Discussionmentioning

confidence: 66%

Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction

et al. 2010

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The overall effect of brain zinc (Zn2+) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn2+ can exacerbate the pathological features of AD, a deficit of Zn2+ intake has also been shown to increase the volume of amyloid plaques in AD transgenic mice. In this study, we investigated the effect of dietary Zn2+ supplementation (30 p.p.m.) in a transgenic mouse model of AD, the 3xTg-AD, that expresses both β amyloid (Aβ)- and tau-dependent pathology. We found that Zn2+ supplementation greatly delays hippocampal-dependent memory deficits and strongly reduces both Aβ and tau pathology in the hippocampus. We also evaluated signs of mitochondrial dysfunction and found that Zn2+ supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn2+ supplementation greatly increases the levels of brain-derived neurotrophic factor (BDNF) of treated 3xTg-AD mice. In summary, our data support the idea that controlling the brain Zn2+ homeostasis may be beneficial in the treatment of AD.

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“…Interestingly, a recent study involving APP/PS1 mice fed a zinc-deficient diet has shown that such a diet increases the plaque volume but does not alter the total plaque number in the brain [27]. Chronic high zinc- or copper-treated mice overexpress APP-C100, which contains Aβ but not the N-terminal zinc and copper binding domain of APP, resulting in reduced soluble Aβ levels but with no changes in the total Aβ levels in the brain [54]. It has also been reported that exposure to copper and, presumably, a mixture of other metals in drinking water results in enhanced Aβ deposition in the brains of rabbits fed a high cholesterol diet [55].…”

Section: Discussionmentioning

confidence: 99%

Zinc Overload Enhances APP Cleavage and Aβ Deposition in the Alzheimer Mouse Brain

Wang

Zheng

et al. 2010

PLoS ONE

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BackgroundAbnormal zinc homeostasis is involved in β-amyloid (Aβ) plaque formation and, therefore, the zinc load is a contributing factor in Alzheimer's disease (AD). However, the involvement of zinc in amyloid precursor protein (APP) processing and Aβ deposition has not been well established in AD animal models in vivo.Methodology/Principal FindingsIn the present study, APP and presenilin 1 (PS1) double transgenic mice were treated with a high dose of zinc (20 mg/ml ZnSO4 in drinking water). This zinc treatment increased APP expression, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory in the transgenic mice. We further examined the effects of zinc overload on APP processing in SHSY-5Y cells overexpressing human APPsw. The zinc enhancement of APP expression and cleavage was further confirmed in vitro.Conclusions/SignificanceThe present data indicate that excess zinc exposure could be a risk factor for AD pathological processes, and alteration of zinc homeostasis is a potential strategy for the prevention and treatment of AD.

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Chronic Exposure to High Levels of Zinc or Copper has Little Effect on Brain Metal Homeostasis or Aβ Accumulation in Transgenic APP-C100 Mice

Cited by 18 publications

References 47 publications

High Dose Zinc Supplementation Induces Hippocampal Zinc Deficiency and Memory Impairment with Inhibition of BDNF Signaling

High Dose Zinc Supplementation Induces Hippocampal Zinc Deficiency and Memory Impairment with Inhibition of BDNF Signaling

Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction

Zinc Overload Enhances APP Cleavage and Aβ Deposition in the Alzheimer Mouse Brain

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