logo logo
Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy. British journal of pharmacology Targeting the amyloid-β (Aβ) peptide cascade has been at the heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached the marketplace based on this hypothesis. Nevertheless, the genetic and other evidence remains strong, if not overwhelming, that Aβ is central to the disease process. Most attention has focused on the biosynthesis of Aβ from its precursor protein through the successive actions of the β- and γ-secretases leading to the development of inhibitors of these membrane proteases. However, the levels of Aβ are maintained through a balance of its biosynthesis and clearance, which occurs both through further proteolysis by a family of amyloid-degrading enzymes (ADEs) and by a variety of transport processes. The development of late-onset AD appears to arise from a failure of these clearance mechanisms rather than by overproduction of the peptide. This review focuses on the nature of these clearance mechanisms, particularly the various proteases known to be involved, and their regulation and potential as therapeutic targets in AD drug development. The majority of the ADEs are zinc metalloproteases [e.g., the neprilysin (NEP) family, insulin-degrading enzyme, and angiotensin converting enzymes (ACE)]. Strategies for up-regulating the expression and activity of these enzymes, such as genetic, epigenetic, stem cell technology, and other pharmacological approaches, will be highlighted. Modifiable physiological mechanisms affecting the efficiency of Aβ clearance, including brain perfusion, obesity, diabetes, and sleep, will also be outlined. These new insights provide optimism for future therapeutic developments in AD research. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc. 10.1111/bph.14593
Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. White Anthony R,Du Tai,Laughton Katrina M,Volitakis Irene,Sharples Robyn A,Xilinas Michel E,Hoke David E,Holsinger R M Damian,Evin Geneviève,Cherny Robert A,Hill Andrew F,Barnham Kevin J,Li Qiao-Xin,Bush Ashley I,Masters Colin L The Journal of biological chemistry Biometals play an important role in Alzheimer disease, and recent reports have described the development of potential therapeutic agents based on modulation of metal bioavailability. The metal ligand clioquinol (CQ) has shown promising results in animal models and small phase clinical trials; however, the actual mode of action in vivo has not been determined. We now report a novel effect of CQ on amyloid beta-peptide (Abeta) metabolism in cell culture. Treatment of Chinese hamster ovary cells overexpressing amyloid precursor protein with CQ and Cu(2+) or Zn(2+) resulted in an approximately 85-90% reduction of secreted Abeta-(1-40) and Abeta-(1-42) compared with untreated controls. Analogous effects were seen in amyloid precursor protein-overexpressing neuroblastoma cells. The secreted Abeta was rapidly degraded through up-regulation of matrix metalloprotease (MMP)-2 and MMP-3 after addition of CQ and Cu(2+). MMP activity was increased through activation of phosphoinositol 3-kinase and JNK. CQ and Cu(2+) also promoted phosphorylation of glycogen synthase kinase-3, and this potentiated activation of JNK and loss of Abeta-(1-40). Our findings identify an alternative mechanism of action for CQ in the reduction of Abeta deposition in the brains of CQ-treated animals and potentially in Alzheimer disease patients. 10.1074/jbc.M602487200
Protection against amyloid beta peptide toxicity by zinc. Lovell M A,Xie C,Markesbery W R Brain research Zinc (Zn) is an essential element in normal development and biology, although it is toxic at high concentrations. Recent studies show that Zn at high concentrations accelerates aggregation of amyloid beta peptide (Abeta), the major component of senile plaques in Alzheimer's disease (AD). This study reports the effect of varying Zn concentrations on Abeta toxicity and the mechanism by which low concentrations function in a protective role. At Abeta/Zn molar ratios of 1:0.1 and 1:0.01, Zn produces significant protection against Abeta toxicity in cultured primary hippocampal neurons. At higher concentrations (1:1 molar ratio), Zn offers no protection or enhances Abeta toxicity. The protective effect of Zn against Abeta toxicity is due in part to the enhancement of Na+/K+ ATPase activity which prevents the disruption of calcium homeostasis and cell death associated with Abeta toxicity. Analysis of Na+/K+ ATPase activity in cultured rat cortical cells indicated that Zn exposure alone afforded a 20% increase in enzyme activity, although the differences were statistically insignificant. However, in cortical cultures exposed to a toxic dose of Abeta (50 microM), Zn at concentrations of 5 and 0.5 microM led to significant increases in Na+/K+ ATPase activity compared with levels in cells treated with Abeta alone. Zn at a 1:1 molar ratio (50 microM) led to a significant decrease in enzyme activity. Together, these data suggest that Zn functions as a double-edged sword, affording protection against Abeta at low concentrations and enhancing toxicity at high concentrations. 10.1016/s0006-8993(99)01114-2
Metal swap between Zn7-metallothionein-3 and amyloid-beta-Cu protects against amyloid-beta toxicity. Meloni Gabriele,Sonois Vanessa,Delaine Tamara,Guilloreau Luc,Gillet Audrey,Teissié Justin,Faller Peter,Vasák Milan Nature chemical biology Aberrant interactions of copper and zinc ions with the amyloid-beta peptide (Abeta) potentiate Alzheimer's disease (AD) by participating in the aggregation process of Abeta and in the generation of reactive oxygen species (ROS). The ROS production and the neurotoxicity of Abeta are associated with copper binding. Metallothionein-3 (Zn(7)MT-3), an intra- and extracellularly occurring metalloprotein, is highly expressed in the brain and downregulated in AD. This protein protects, by an unknown mechanism, cultured neurons from the toxicity of Abeta. Here, we show that a metal swap between Zn(7)MT-3 and soluble and aggregated Abeta(1-40)-Cu(II) abolishes the ROS production and the related cellular toxicity. In this process, copper is reduced by the protein thiolates forming Cu(I)(4)Zn(4)MT-3, in which an air-stable Cu(I)(4)-thiolate cluster and two disulfide bonds are present. The discovered protective effect of Zn(7)MT-3 from the copper-mediated Abeta(1-40) toxicity may lead to new therapeutic strategies for treating AD. 10.1038/nchembio.89
Alzheimer's disease & metals: therapeutic opportunities. Kenche Vijaya B,Barnham Kevin J British journal of pharmacology Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called 'metal protein attenuating compound' approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD. 10.1111/j.1476-5381.2011.01221.x
The effect of Cu(2+) and Zn(2+) on the Aβ42 peptide aggregation and cellular toxicity. Sharma Anuj K,Pavlova Stephanie T,Kim Jaekwang,Kim Jungsu,Mirica Liviu M Metallomics : integrated biometal science The coordination chemistry of Cu and Zn metal ions with the amyloid β (Aβ) peptides has attracted a lot of attention in recent years due to its implications in Alzheimer's disease. A number of reports indicate that Cu and Zn have profound effects on Aβ aggregation. However, the impact of these metal ions on Aβ oligomerization and fibrillization is still not well understood, especially for the more rapidly aggregating and more neurotoxic Aβ42 peptide. Here we report the effect of Cu(2+) and Zn(2+) on Aβ42 oligomerization and aggregation using a series of methods such as Thioflavin T (ThT) fluorescence, native gel and Western blotting, transmission electron microscopy (TEM), and cellular toxicity studies. Our studies suggest that both Cu(2+) and Zn(2+) ions inhibit Aβ42 fibrillization. While presence of Cu(2+) stabilizes Aβ42 oligomers, Zn(2+) leads to formation of amorphous, non-fibrillar aggregates. The effects of temperature, buffer, and metal ion concentration and stoichiometry were also studied. Interestingly, while Cu(2+) increases the Aβ42-induced cell toxicity, Zn(2+) causes a significant decrease in Aβ42 neurotoxicity. While previous reports have indicated that Cu(2+) can disrupt β-sheets and lead to non-fibrillar Aβ aggregates, the neurotoxic consequences were not investigated in detail. The data presented herein including cellular toxicity studies strongly suggest that Cu(2+) increases the neurotoxicity of Aβ42 due to stabilization of soluble Aβ42 oligomers. 10.1039/c3mt00161j
Protective effect of zinc on amyloid-beta 25-35 and 1-40 mediated toxicity. Neurotoxicity research Amyloid beta-peptide (Abeta) is widely held to be associated with Alzheimer's disease, the insoluble aggregates of the peptide being the major constituents of senile plaques. In this study, we evaluated the effect of Zn(2+) (5, 50 and 200 microM) on Abeta induced toxicity using the human teratocarcinome (NT2) cell line. Our results proved that 50 and 200 microM Zn(2+) protected NT2 cells from Abeta 25-35 toxicity. Zinc was also shown to be effective by preventing the loss of mitochondrial membrane potential (DeltaPsi(m)) induced by Abeta 25-35, not allowing cytochrome c release from mitochondria, and subsequently, caspase 3 activation. However, when the cells were treated with Abeta 1-40, only Zn(2+) 5 microM had a protective effect. We have further observed that 5 microM Zn(2+) prevented Abeta 1-40 aggregation into a beta-sheet structure. Considering the results presented, we argue that Zn(2+) has a concentration-dependent protective effect. 10.1007/BF03033885
Zinc lowers amyloid-beta toxicity by selectively precipitating aggregation intermediates. Garai K,Sahoo B,Kaushalya S K,Desai R,Maiti S Biochemistry Soluble amyloid-beta (Abeta) aggregates are suspected to play a major role in Alzheimer's disease. Zn2+ at a concentration of a few micromolar, which is too dilute to affect the precipitation equilibrium of Abeta, can destabilize these aggregates [Garai, K., Sengupta, P., Sahoo, B., and Maiti, S. (2006) Biochem. Biophys. Res. Commun. 345, 210-215]. Here we investigate the nature of these aggregates in the context of the precipitation pathway, the mechanism underlying their destabilization, and the biological consequences of this destabilization. We show that the larger soluble aggregates (size >10 nm) form only in supersaturated Abeta solutions, implying that they are intermediates in the pathway toward fibril formation. We also show that Zn2+ destabilizes these intermediates by accelerating their aggregation kinetics. The resulting change in the size distribution of the Abeta solution is sufficient to eliminate its toxicity to cultured mammalian neurons. Our results provide an explanation for the existing observations that Zn2+ at a concentration of a few micromolar significantly reduces Abeta toxicity. 10.1021/bi700798b
The Extracellular Zn Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid-β Revealed by a Nanowire Transistor. Anand Ankur,Chi Chih-Hung,Banerjee Subhasree,Chou Ming-Yi,Tseng Fan-Gang,Pan Chien-Yuan,Chen Yit-Tsong Small (Weinheim an der Bergstrasse, Germany) The Zn stored in the secretory vesicles of glutamatergic neurons is coreleased with glutamate upon stimulation, resulting in the elevation of extracellular Zn concentration (CZn2+ex). This elevation of CZn2+ex regulates the neurotransmission and facilitates the fibrilization of amyloid-β (Aβ). However, the exact CZn2+ex surrounding neurons under (patho)physiological conditions is not clear and the connection between CZn2+ex and the Aβ fibrilization remains obscure. Here, a silicon nanowire field-effect transistor (SiNW-FET) with the Zn -sensitive fluorophore, FluoZin-3 (FZ-3), to quantify the CZn2+ex in real time is modified. This FZ-3/SiNW-FET device has a dissociation constant of ≈12 × 10 m against Zn . By placing a coverslip seeded with cultured embryonic cortical neurons atop an FZ-3/SiNW-FET, the CZn2+ex elevated to ≈110 × 10 m upon stimulation with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Blockers against the AMPA receptor or exocytosis greatly suppress this elevation, indicating that the Zn stored in the synaptic vesicles is the major source responsible for this elevation of CZn2+ex. In addition, a SiNW-FET modified with Aβ could bind Zn with a dissociation constant of ≈633 × 10 m and respond to the Zn released from AMPA-stimulated neurons. Therefore, the CZn2+ex can reach a level high enough to bind Aβ and the Zn homeostasis can be a therapeutic strategy to prevent neurodegeneration. 10.1002/smll.201704439
Dietary zinc supplementation of 3xTg-AD mice increases BDNF levels and prevents cognitive deficits as well as mitochondrial dysfunction. Corona C,Masciopinto F,Silvestri E,Viscovo A Del,Lattanzio R,Sorda R La,Ciavardelli D,Goglia F,Piantelli M,Canzoniero L M T,Sensi S L Cell death & disease The overall effect of brain zinc (Zn(2+)) in the progression and development of Alzheimer's disease (AD) is still not completely understood. Although an excess of Zn(2+) can exacerbate the pathological features of AD, a deficit of Zn(2+) 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 Zn(2+) 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 Zn(2+) 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 Zn(2+) supplementation prevents the age-dependent respiratory deficits we observed in untreated 3xTg-AD mice. Finally, we found that Zn(2+) 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 Zn(2+) homeostasis may be beneficial in the treatment of AD. 10.1038/cddis.2010.73
Zinc Inhibits Amyloid beta Production from Alzheimer's Amyloid Precursor Protein in SH-SY5Y Cells. Lee Jinu,Kim Chul Hoon,Kim Dong Goo,Ahn Young Soo The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology Zinc released from excited glutamatergic neurons accelerates amyloid beta (Abeta) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter Abeta concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed Abeta production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased Abeta40 and Abeta42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both beta- and alpha-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of Abeta40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of Abeta secretion. 10.4196/kjpp.2009.13.3.195
Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions. Tian Zhi-Ying,Wang Chun-Yan,Wang Tao,Li Yan-Chun,Wang Zhan-You Aging and disease Evidence has been accumulating that zinc ions can trigger β-amyloid (Aβ) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer's disease (AD). Chelating zinc inhibits Aβ aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic Ca/Zn-binding protein found only in a small number of astrocytes in the normal brain. However, in the AD brain, S100A6 is highly expressed in astrocytes around Aβ plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on Aβ plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased Aβ deposition and S100A6 expression, both reversible by the zinc chelator clioquinol, in the brains of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice. To examine whether exogenous S100A6 could induce Aβ plaque disaggregation through competition for zinc in vitro, we incubated APP/PS1 mouse brain sections with recombinant human S100A6 protein or co-incubated them with human S100A6-expressing cells. Both treatments efficiently reduced the Aβ plaque burden in situ. In addition, treatment with exogenous S100A6 protected cultured COS-7 cells against zinc toxicity. Our results show for the first time that increased S100A6 levels correlate with both Aβ disaggregation and decrease of Aβ plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from Aβ deposition through zinc sequestration. 10.14336/AD.2018.0912
Chronic exposure to high levels of zinc or copper has little effect on brain metal homeostasis or Abeta accumulation in transgenic APP-C100 mice. Maynard Christa J,Cappai Roberto,Volitakis Irene,Laughton Katrina M,Masters Colin L,Bush Ashley I,Li Qiao-Xin Cellular and molecular neurobiology Aberrant metal homeostasis may enhance the formation of reactive oxygen species and Abeta oligomerization and may therefore be a contributing factor in Alzheimer's disease. This study investigated the effect of chronic high intake of dietary Zn or Cu on brain metal levels and the accumulation and solubility of Abeta in vivo, using a transgenic mouse model that over expresses the C-terminal containing Abeta fragment of human amyloid precursor protein but does not develop amyloid deposits. Exposure to chronic high Zn or Cu in the drinking water resulted in only slight elevations of the respective metals in the brain. Total Abeta levels were unchanged although soluble Abeta levels were slightly decreased, without visible plaque formation, enhanced gliosis, antioxidant upregulation or neuronal loss. This study indicates that brain metal levels are only marginally altered by long term oral exposure to extremely high Cu or Zn levels, and that this does not induce Abeta-amyloid formation in human Abeta expressing, amyloid-free mice, although this is sufficient to modulate Abeta solubility in vivo. 10.1007/s10571-009-9401-7
Aluminum, copper, iron and zinc differentially alter amyloid-Aβ(1-42) aggregation and toxicity. Bolognin Silvia,Messori Luigi,Drago Denise,Gabbiani Chiara,Cendron Laura,Zatta Paolo The international journal of biochemistry & cell biology Amyloid-β(1-42) (Aβ) is believed to play a crucial role in the ethiopathogenesis of Alzheimer's Disease (AD). In particular, its interactions with biologically relevant metal ions may lead to the formation of highly neurotoxic complexes. Here we describe the species that are formed upon reacting Aβ with several biometals, namely copper, zinc, iron, and with non-physiological aluminum to assess whether different metal ions are able to differently drive Aβ aggregation. The nature of the resulting Aβ-metal complexes and of the respective aggregates was ascertained through a number of biophysical techniques, including electrospray ionization mass spectrometry, dynamic light scattering, fluorescence, transmission electron microscopy and by the use of conformation-sensitive antibodies (OC, αAPF). Metal binding to Aβ is shown to confer highly different chemical properties to the resulting complexes; accordingly, their overall aggregation behaviour was deeply modified. Both aluminum(III) and iron(III) ions were found to induce peculiar aggregation properties, ultimately leading to the formation of annular protofibrils and of fibrillar oligomers. Notably, only Aβ-aluminum was characterized by the presence of a relevant percentage of aggregates with a mean radius slightly smaller than 30 nm. In contrast, both zinc(II) and copper(II) ions completely prevented the formation of soluble fibrillary aggregates. The biological effects of the various Aβ-metal complexes were studied in neuroblastoma cell cultures: Aβ-aluminum turned out to be the only species capable of triggering amyloid precursor and tau181 protein overproduction. Our results point out that Al can effectively interact with Aβ, forming "structured" aggregates with peculiar biophysical properties which are associated with a high neurotoxicity. 10.1016/j.biocel.2011.02.009
Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production. Gerber Hermeto,Wu Fang,Dimitrov Mitko,Garcia Osuna Guillermo M,Fraering Patrick C The Journal of biological chemistry Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid-β peptide (Aβ). However, little is known about whether these biometals modulate the generation of Aβ. In the present study we demonstrate in both cell-free and cell-based assays that zinc and copper regulate Aβ production by distinct molecular mechanisms affecting the processing by γ-secretase of its Aβ precursor protein substrate APP-C99. We found that Zn induces APP-C99 dimerization, which prevents its cleavage by γ-secretase and Aβ production, with an IC value of 15 μm Importantly, at this concentration, Zn also drastically raised the production of the aggregation-prone Aβ43 found in the senile plaques of AD brains and elevated the Aβ43:Aβ40 ratio, a promising biomarker for neurotoxicity and AD. We further demonstrate that the APP-C99 histidine residues His-6, His-13, and His-14 control the Zn-dependent APP-C99 dimerization and inhibition of Aβ production, whereas the increased Aβ43:Aβ40 ratio is substrate dimerization-independent and involves the known Zn binding lysine Lys-28 residue that orientates the APP-C99 transmembrane domain within the lipid bilayer. Unlike zinc, copper inhibited Aβ production by directly targeting the subunits presenilin and nicastrin in the γ-secretase complex. Altogether, our data demonstrate that zinc and copper differentially modulate Aβ production. They further suggest that dimerization of APP-C99 or the specific targeting of individual residues regulating the production of the long, toxic Aβ species, may offer two therapeutic strategies for preventing AD. 10.1074/jbc.M116.754101
NMR metabolomic investigation of astrocytes interacted with Aβ₄₂ or its complexes with either copper(II) or zinc(II). Rocchi Altea,Valensin Daniela,Aldinucci Carlo,Giani Gabriele,Barbucci Rolando,Gaggelli Elena,Kozlowski Henryk,Valensin Gianni Journal of inorganic biochemistry Alzheimer's disease (AD) is the leading cause of senile dementia. One of the main hallmarks of AD is the presence of amyloid plaques in the brain, primarily formed by fibrils of the amyloid-β (Aβ) peptide. Transition metal ions, such as Cu(2+) and Zn(2+) have been found at high concentrations in senile plaques isolated from AD patients and evidence have been reached that (i) Aβ aggregation is greatly affected by Cu(2+) and Zn(2+) and (ii) Cu(2+), implicated in the formation of reactive oxygen species, leads to mitochondrial dysfunctions ultimately leading to neuronal cells death. Aβ, apart from being toxic to neural cells, induces reactive astrocytosis in cell culture. Astrocytes play many crucial roles to sustain normal brain function by maintaining the cerebral homeostasis, modulating the synaptic transmission, and providing a metabolic support for neuronal growth. Although many studies have shown that Aβ fibrils interfere in the main astrocytic functions aimed at supporting the neuronal activity, nothing is known about the effects of Zn(2+)- and Cu(2+)-induced Aβ aggregates on astrocyte functions. In this study the effects of treatments with Aβ(42), either in absence or in the presence of Cu(2+) and Zn(2+), on astrocyte cell cultures were evaluated by using classical cellular assay and by looking at changes in metabolic profiles in the cellular medium by using nuclear magnetic resonance spectroscopy (NMR). Our results indicate that metal induced Aβ aggregation strongly affects the metabolites involved in the neurotransmission activity supporting a deleterious impact of Cu(2+) and Zn(2+) Aβ amyloidogenesis on astrocyte functions. 10.1016/j.jinorgbio.2012.08.021
Metal ions influx is a double edged sword for the pathogenesis of Alzheimer's disease. Wang Pu,Wang Zhan-You Ageing research reviews Alzheimer's disease (AD) is a common form of dementia in aged people, which is defined by two pathological characteristics: β-amyloid protein (Aβ) deposition and tau hyperphosphorylation. Although the mechanisms of AD development are still being debated, a series of evidence supports the idea that metals, such as copper, iron, zinc, magnesium and aluminium, are involved in the pathogenesis of the disease. In particular, the processes of Aβ deposition in senile plaques (SP) and the inclusion of phosphorylated tau in neurofibrillary tangles (NFTs) are markedly influenced by alterations in the homeostasis of the aforementioned metal ions. Moreover, the mechanisms of oxidative stress, synaptic plasticity, neurotoxicity, autophagy and apoptosis mediate the effects of metal ions-induced the aggregation state of Aβ and phosphorylated tau on AD development. More importantly, imbalance of these mechanisms finally caused cognitive decline in different experiment models. Collectively, reconstructing the signaling network that regulates AD progression by metal ions may provide novel insights for developing chelators specific for metal ions to combat AD. 10.1016/j.arr.2016.10.003
Relationship of Serum Glycemic Status with Serum Zinc Level in Type 2 Diabetes Mellitus. Eva H,Akter Q S,Alam M K Mymensingh medical journal : MMJ Association of increased diabetes related complication and higher glycemic status in patients with type 2 diabetes mellitus (DM) has been well recognized. This cross sectional study was carried out to assess serum zinc (Zn) level and its relationship to glycemic status in type 2 DM patients and conducted in the Department of Physiology, Dhaka Medical College, Dhaka, Bangladesh from July 2014 to June 2015. Fifty (50) type 2 diabetic subjects with age ranging from 40 to 55 years were study group and fifty healthy subjects matched by ages and BMI were control group. Study population was chosen from Bangladesh Institute of Research for Diabetic Endocrine and Metabolic Disorders (BIRDEM) General Hospital, Dhaka, Bangladesh. Glycated hemoglobin (HbA1c) and fasting serum glucose (FSG) levels were estimated in the laboratory of the Department of Biochemistry, BIRDEM General Hospital, Dhaka, Bangladesh. Serum Zn level was estimated by flame atomic absorption spectrophotometry. For statistical analysis unpaired Student's 't' test was performed. In this study, mean serum zinc level was significantly (p<0.001) lower in patients than that of control group. On correlation analysis, serum Zn level showed significant negative correlation with FSG and HbA1C levels in type 2 diabetic patients. The results conclude that serum Zn level was reduced in DM which was higher with glycemic status of this disease.
Evaluation of Serum Zinc Status and Glycated Hemoglobin in Patients with Type-2 Diabetes Mellitus. Israt S,Nessa A,Rahman H H,Sharmin A,Akter N,Dipa M I,Firoz S,Islam M F Mymensingh medical journal : MMJ Type-2 diabetes is the most common type of diabetes, accounting for about 90% of all diabetes. This study was done to assess the Serum Zinc status and Glycated Hemoglobin in type-2 diabetic patients in order to compare this parameter with healthy subjects. This analytical type of cross sectional study was carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh from July 2018 to June 2019. A total number of 140 subjects, age was ranged from 35-65 years were included in this study. Among them, seventy (70) type-2 diabetic patients were taken as study group (Group II) and seventy (70) age matched healthy subjects were taken as control group (Group I). Group I again subdivided into control group male (Group IA) and control group female (Group IB). Group II also subdivided into study group male (Group IIA) and study group female (Group IIB). Data were expressed as mean±SE and statistical significance of difference among the group was calculated by unpaired students' 't' test. Therefore, by this study we recommended that routine estimation of this parameter is important for prevention of complication related to diabetes for leading a healthy life.
Interrelationships among mediators of cellular zinc homeostasis in healthy and type 2 diabetes mellitus populations. Chu Anna,Foster Meika,Hancock Dale,Petocz Peter,Samman Samir Molecular nutrition & food research SCOPE:The involvement of zinc in multiple physiological systems requires tight control of cellular zinc concentration. This study aims to explore the relationships among selected mediators of cellular zinc homeostasis in an apparently healthy (AH) population and a cohort with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS:Baseline data of three trials forming two cohorts, AH (n = 70) and T2DM (n = 42), were used for multivariate analyses to identify groupings within ten zinc transporter and metallothionein (MT) gene expressions, stratified by health status. Multiple regression models were used to explore relationships among zinc transporter/MT groupings and plasma zinc. Gene expression of zinc transporters and MTs, with the exception of ZnT6, were significantly lower in the T2DM cohort (p < 0.01). Cluster analysis showed that the groupings of zinc transporters and MTs were largely similar between the two cohorts, with the exception for ZnT1 and ZIP7. Zinc transporters and MTs were significant determinants of plasma zinc (r = 0.48, p = 0.001) in the AH cohort, but not in the T2DM cohort. CONCLUSION:The current study suggests altered cellular zinc homeostasis in T2DM and supports the use of multiple zinc transporters and MTs groupings to further understand zinc homeostasis in health and T2DM. 10.1002/mnfr.201600838
Zinc and diabetes mellitus: understanding molecular mechanisms and clinical implications. Ranasinghe Priyanga,Pigera Shehani,Galappatthy Priyadarshani,Katulanda Prasad,Constantine Godwin R Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences BACKGROUND:Diabetes mellitus is a leading cause of morbidity and mortality worldwide. Studies have shown that Zinc has numerous beneficial effects in both type-1 and type-2 diabetes. We aim to evaluate the literature on the mechanisms and molecular level effects of Zinc on glycaemic control, β-cell function, pathogenesis of diabetes and its complications. METHODS:A review of published studies reporting mechanisms of action of Zinc in diabetes was undertaken in PubMed and SciVerse Scopus medical databases using the following search terms in article title, abstract or keywords; ("Zinc" or "Zn") and ("mechanism" or "mechanism of action" or "action" or "effect" or "pathogenesis" or "pathology" or "physiology" or "metabolism") and ("diabetes" or "prediabetes" or "sugar" or "glucose" or "insulin"). RESULTS:The literature search identified the following number of articles in the two databases; PubMed (n = 1799) and SciVerse Scopus (n = 1879). After removing duplicates the total number of articles included in the present review is 111. Our results show that Zinc plays an important role in β-cell function, insulin action, glucose homeostasis and the pathogenesis of diabetes and its complications. CONCLUSION:Numerous in-vitro and in-vivo studies have shown that Zinc has beneficial effects in both type-1 and type-2 diabetes. However further randomized double-blinded placebo-controlled clinical trials conducted for an adequate duration, are required to establish therapeutic safety in humans. 10.1186/s40199-015-0127-4