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

Corona, Carlo; Masciopinto, Francesca; Silvestri, Elena; Viscovo, Adelaide Del; Lattanzio, Rossano; Sorda, Rossana La; Ciavardelli, Domenico; Goglia, Fernando; Piantelli, Mauro; Canzoniero, Lorella M.T.; Sensi, Stefano L.

doi:10.1038/cddis.2010.73

Cited by 161 publications

(135 citation statements)

References 39 publications

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“…Conversely, Zn 2+ supplementation for 3 x TG-AD transgenic mice actually attenuated disease pathology [27]. In support of this mice depleted of synaptic Zn 2+ through a ZnT3 knockout mutation present agedependent memory impairments similar to those observed in Alzheimer's disease models [28]; this is particularly significant as the authors found that ZnT3 levels decline in humans with aging, particularly those with Alzheimer's disease [29].…”

Section: Introductionmentioning

confidence: 90%

“…Alzheimer's like symptoms in animal studies [24,25,27,29], as not only is Aβ misfolding extremely sensitive to Zn 2+ , but also to the ratio of Aβ and Zn 2+ as well as its interplay with Cu 2+ . It has recently been shown that physiologically relevant N-terminally truncated forms of A have a femto-molar affinity for Cu 2+ [70], it remains to be established what impact Zn 2+ might have on these very tightly bound Cu 2+ complexes.…”

Section: Contrasting and Dominating Influence Of Zn 2+ Over Cu 2+ In mentioning

confidence: 98%

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The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

Matheou

Younan

Viles

2016

Journal of Molecular Biology

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The misfolding and self-assembly of amyloid-β (Aβ) into oligomers and fibres is fundamental to Alzheimer's disease pathology. Alzheimer's disease is a multifaceted disease. One factor that is thought to have a significant role in disease aetiology is Zn(2+) homeostasis, which is disrupted in the brains of Alzheimer's disease sufferers and has been shown to modulate Alzheimer's symptoms in animal models. Here, we investigate how the kinetics of Aβ fibre growth are affected at a range of Zn(2+) concentrations and we use transmission electron microscopy to characterise the aggregate assemblies formed. We demonstrate that for Aβ(1-40), and Aβ(1-42), as little as 0.01mol equivalent of Zn(2+) (100nM) is sufficient to greatly perturb the formation of amyloid fibres irreversibly. Instead, Aβ(1-40) assembles into short, rod-like structures that pack tightly together into ordered stacks, whereas Aβ(1-42) forms short, crooked assemblies that knit together to form a mesh of disordered tangles. Our data suggest that a small number of Zn(2+) ions are able to influence a great many Aβ molecules through the rapid exchange of Zn(2+) between Aβ peptides. Surprisingly, although Cu(2+) binds to Aβ 10,000 times tighter than Zn(2+), the effect of Zn(2+) on Aβ assembly dominates in Cu(2+)/Zn(2+) mixtures, suggesting that trace levels of Zn(2+) must have a profound effect on extracellular Aβ accumulation. Trace Zn(2+) levels profoundly influence Aβ assembly even at concentrations weaker than its affinity for Aβ. These observations indicate that inhibitors of fibre assembly do not necessarily have to be at high concentration and affinity to have a profound impact.

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Section: Introductionmentioning

confidence: 90%

Section: Contrasting and Dominating Influence Of Zn 2+ Over Cu 2+ In mentioning

confidence: 98%

The Rapid Exchange of Zinc2+ Enables Trace Levels to Profoundly Influence Amyloid-β Misfolding and Dominates Assembly Outcomes in Cu2+/Zn2+ Mixtures

Matheou

Younan

Viles

2016

Journal of Molecular Biology

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“…Furthermore, post hoc analysis revealed a statistically significant reduction of cognitive decline on two tests (and nearly significant for the MMSE) when analyses were limited to the twenty-nine patients over seventy years old (Brewer 2012). Furthermore, dietary zinc deficiency exacerbated behavioral and histological pathology in an APP mutant mouse (Stoltenberg et al 2007), and zinc supplementation prevented AD pathology in the 3X-Tg mouse model (Corona et al 2010). However, another study found impaired memory performance in zinc supplemented APP mutant mice associated with decreased Ab deposition (Linkous et al 2009).…”

Section: Therapies Aimed At Modulating Zinc Availabilitymentioning

confidence: 96%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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“…Levels of BDNF and NGF have been shown to decrease in zinc(II) deficient mice [125], hence zinc(II) dietary supplementation seems to replenish the NGF [126], as well as the BDNF, level [127]. Moreover, chronic treatments with zinc(II) ion induced a BDNF mRNA upregulation in the cortex and hippocampus [128], strongly suggesting a more direct role of this metal ion in the neurotrophins expression.…”

Section: Metals and Neurotrophinsmentioning

confidence: 96%