Zinc Status Alters Alzheimer's Disease Progression through NLRP3-Dependent Inflammation

Rivers-Auty, Jack; Tapia, Víctor S.; White, Charles A.; Daniels, Michael J.; Drinkall, Samuel; Kennedy, Paul; Spence, Harry G.; Yu, Shaojun; Green, Jack; Hoyle, Christopher; Cook, James; Bradley, Amy; Mather, Alison E.; Peters, Ruth; Tzeng, Te‐Chen; Gordon, Margaret Jane; Beattie, John; Brough, David; Lawrence, Catherine B.

doi:10.1523/jneurosci.1980-20.2020

Cited by 49 publications

(34 citation statements)

References 46 publications

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“…Decreased bioavailability of Zn and may lead to NLRP3-driven inflammation. This is also evident in Alzheimer's diseases and leads to cognitive decline in animal models, which may translate to ASD models (Pellegrini et al, 2020;Rivers-Auty et al, 2021). Increased cytokine expression and the activation of glial cells have been linked to synapse loss and modification of synaptic function (Kim et al, 2020).…”

Section: Inflammasomicsmentioning

confidence: 99%

The Metallome as a Link Between the “Omes” in Autism Spectrum Disorders

Stanton

Malijauskaite

McGourty

et al. 2021

Front. Mol. Neurosci.

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Metal dyshomeostasis plays a significant role in various neurological diseases such as Alzheimer’s disease, Parkinson’s disease, Autism Spectrum Disorders (ASD), and many more. Like studies investigating the proteome, transcriptome, epigenome, microbiome, etc., for years, metallomics studies have focused on data from their domain, i.e., trace metal composition, only. Still, few have considered the links between other “omes,” which may together result in an individual’s specific pathologies. In particular, ASD have been reported to have multitudes of possible causal effects. Metallomics data focusing on metal deficiencies and dyshomeostasis can be linked to functions of metalloenzymes, metal transporters, and transcription factors, thus affecting the proteome and transcriptome. Furthermore, recent studies in ASD have emphasized the gut-brain axis, with alterations in the microbiome being linked to changes in the metabolome and inflammatory processes. However, the microbiome and other “omes” are heavily influenced by the metallome. Thus, here, we will summarize the known implications of a changed metallome for other “omes” in the body in the context of “omics” studies in ASD. We will highlight possible connections and propose a model that may explain the so far independently reported pathologies in ASD.

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Section: Inflammasomicsmentioning

confidence: 99%

The Metallome as a Link Between the “Omes” in Autism Spectrum Disorders

Stanton

Malijauskaite

McGourty

et al. 2021

Front. Mol. Neurosci.

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“…In addition to affecting synaptic function, zinc has been shown linked with oxidative stress as well as neuroin ammation that are important in AD disease development [11]. In the present study, pretreatment of SH-SY5Y cells by emodin suppressed the zinc-induced ROS generation, reduced the formation of lipid peroxidation product (4-HNE), and decreased the level of DNA damage marker (8-OHdG).…”

Section: Discussionmentioning

confidence: 52%

“…The synergistic interaction between Zn 2+ and reactive oxygen species (ROS) has been shown to amplify the ischemic brain injury in rodent model [9] through direct ROS generation or through, mitochondrial Ca 2+ uniporter [10]. Recent study indicates that zinc status introduce through In ammation through NLRP3-mediated pathway [11].…”

Section: Introductionmentioning

confidence: 99%

Emodin Protects SH-SY5Y Cells Against Zinc-Induced Synaptic Impairment and Oxidative Stress Through ERK1/2 Pathway

Chen¹,

Lai²,

Chen³

et al. 2021

Preprint

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Background: Zinc is an essential trace element important for the physiological function of the central nervous system. The abnormal accumulation of zinc inside neurons may induce mitochondrial dysfunction and oxidative stress which contributes to many brain diseases. We hypothesized that natural anthraquinone derivative emodin can protect against neurotoxicity induced by pathological concentrations of zinc via Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, and alleviate the oxidative stress and mitochondria dysfunction. Results: Human neuroblastoma (SH-SY5Y cells) was treated with zinc sulfate and different concentrations of emodin, and was examined in the changes in the levels of ERK1/2 expressions, oxidative stress (DCFH-DA staining), mitochondrial function (JC-1 staining), and lipid peroxidation (4-hydroxynonenal staining), and DNA oxidation (8-Hydroxy-2-deoxyguanosine staining). Emodin ameliorated zinc-induced altered expression level of phosphorylated-ERK1/2 (not total-ERK1/2), and synaptic proteins (presynaptic SNAP25, synaptophysin and postsynaptic PSD95) in SH-SY5Y cells, in a dose-dependent manor. Moreover, emodin inhibited the generation of reactive oxygen substrates, oxidative stress, facilitated the collapse of mitochondrial membrane potential (ΔΨm) in SH-SY5Y cells. Conclusion: Our results indicated that emodin exerts neuroprotective effects against zinc by normalizing synaptic impairment via decreasing the phosphorylation of ERK1/2, reducing reactive oxygen substrates and protecting mitochondrial function.

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“…It has been long known that trace metals, such as zinc, are impacting on protein aggregation, synaptic signaling, mitochondrial function, oxidative stress and inflammation, ultimately resulting in synapse dysfunction and neuronal loss in the AD brain. 61 It was shown that zinc status alters AD progression through NLRP3-dependent inflammation, 62 and zinc dyshomeostasis has been reported in the plasma of AD patients. 63 Another intriguing finding was the very significant contribution of helix-loop-helix transcription factors to the dysregulated redox gene expression pattern.…”

Section: Discussionmentioning

confidence: 99%