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  • 1
    Online Resource
    Online Resource
    San Diego :Elsevier Science & Technology,
    Keywords: Metals in the body. ; Electronic books.
    Type of Medium: Online Resource
    Pages: 1 online resource (468 pages)
    Edition: 1st ed.
    ISBN: 9780128045633
    DDC: 612.3/924
    Language: English
    Note: Cover -- Title page -- Copyright page -- Contents -- Contributors -- Preface -- Chapter 1 - Biometals and Alzheimer's Disease -- Introduction -- The Role of Copper in AD -- The Role of Zinc in AD -- The Role of Iron in AD -- Therapeutic Targeting of Biometals in AD -- Conclusions -- References -- Chapter 2 - Copper in Alzheimer's Disease -- Introduction -- The Physiology of Copper -- Copper Absorption and Distribution -- Copper in the Liver -- Copper's Path From General Circulation to the Brain -- The Key Role of Ceruloplasmin -- Copper Toxicity -- The Role of Copper in Alzheimer's Disease -- Genetics of Copper and AD -- The AD Copper Subtype -- Conclusions -- References -- Chapter 3 - The Role of Selenium in Neurodegenerative Diseases -- Introduction -- Selenoproteins and the Selenoproteome -- Selenium and Alzheimer's Disease -- Parkinson's Disease -- Other Neurodegenerative Diseases -- Conclusions -- References -- Chapter 4 - Does HFE Genotype Impact Macrophage Phenotype in Disease Process and Therapeutic Response? -- Iron -- Hemochromatosis -- Discovery -- Types -- HFE -- Structure -- Function -- Polymorphisms -- Macrophages -- Macrophage and Iron Metabolism -- Macrophage Polarization -- Macrophages and HFE -- HFE and Neurodegenerative Diseases -- Alzheimer's Disease -- Amyotrophic Lateral Sclerosis -- Parkinson's Disease -- HFE and Cancer -- HFE Animal Models -- Conclusions -- References -- Chapter 5 - Chemical Elements and Oxidative Status in Neuroinflammation -- Introduction -- Metal-Induced Neurotoxicity and Multiple Sclerosis -- Metals and Oxidative Status in Multiple Sclerosis -- Metals and Oxidative Status in Clinically Isolated Syndromes -- Conclusions -- References -- Chapter 6 - Metals and Neuroinflammation -- Introduction -- Mechanisms by Which Metal Elements Can Incite Immune Activity -- Metals as Haptens. , Metal Elements with Valence Instability -- Copper (Cu) -- Iron (Fe) -- Manganese -- Metals Attaching to Sulfhydryl Residues -- Lead (Pb) -- Mercury (Hg) -- Metals Associated with Particulate and Colloidal Materials -- Aluminum (Al) -- Titanium, Silver and Gold (Ti, Ag, Au) -- Metals Which Lead to Oxidative Stress and Inflammation by Means that are not yet Understood -- The Relation Between Reactive Oxygen and Nitrogen Species and Inflammation -- Conclusions -- References -- Chapter 7 - Metals and Prions: Twenty Years of Mining the Awe -- Prion Diseases -- Prion Protein -- Prion Protein Function -- Copper and PrP -- Zinc and PrP -- Iron and PrP -- Manganese and PrP -- Metals in Prion Disease -- Chelation Therapy and Prion Disease -- Conclusions -- References -- Chapter 8 - Manganese and Neurodegeneration -- Background -- Mn Essentiality and Metabolic Functions -- Mn Biokinetics and Homeostatic Control -- Routes and Sources of Mn Exposure -- Absorption of Airborne Mn -- Parenteral Exposure to Mn -- Oral Absorption of Mn From Food and Water -- Mn Biodistribution and Elimination -- Biokinetics of Mn in Brain -- Mn Transport Into Brain -- Regional Delivery of Mn in the Brain -- Mn Elimination From Brain Compartment -- Subcellular Distribution of Mn in Brain -- Homeostatic Control of Mn -- Influence of Age and Gender on Mn Metabolism -- Influence of Age on Mn Metabolism -- Influence of Gender on Mn Metabolism -- Toxicological Evaluation Mn Levels in Nutrition -- Neurotoxicology of Mn -- Deficient Exposure -- Mn Overexposure -- Clinical Features -- Modulating Factors of Mn Induced Neurotoxicity -- Mn dosage -- Duration of Mn supplementation -- Co-morbidities associated with Mn exposure -- Neuropathological Features -- Selected Mechanisms of Mn-Induced Neurotoxicity -- Alterations of Glutamatergic, GABAergic and dopaminergic (DAergic) systems. , Impaired Energy Metabolism -- Oxidative stress -- Biomonitoring of Mn in Patients Undergoing PN -- Biomarkers of Exposure, Effect, and Susceptibility -- Classical Approach of Mn Biomonitoring in PN Patients: Biomarkers of Exposure -- Mn Concentration in Body Fluids -- Magnetic Resonance Imaging (MRI) -- Alternative Approaches: Subclinical Biomarkers Predictive of Mn-Induced Neurotoxicity -- Neurobehavioral Tests -- Neuroimaging Biomarker: 1H Proton Magnetic Resonance Spectroscopy -- Hematologic and Urinary Biomarkers Related to Catecholaminergic System -- Conclusions -- Acknowledgment -- References -- Chapter 9 - Zinc in Autism -- Introduction -- Zinc signaling in autism -- Zinc and Inflammatory Processes in Autism -- Zinc and Synaptic Dysfunction in Autism-Molecular Pathways -- Therapeutic Strategies in Autism Based on Biometals -- Conclusions -- References -- Chapter 10 - Metals and Motor Neuron Disease -- List of Abbreviations -- Introduction -- Metal Exposure -- Metals in ALS Cerebrospinal Fluid -- Metals in ALS -- Protection by Metallothionein -- Metal Distribution in ALS -- Metal Related ALS Clusters -- ALS and Occupational Exposures to Metals -- Conjugal ALS -- Genetic Aspects -- Concluding Remarks -- References -- Chapter 11 - Metals and Lysosomal Storage Disorders -- Introduction -- Common Pathological Features of Lysosomal Storage Disorders -- Endosomal-Autophagic-Lysosomal System -- Lysosomal Dysfunction in LSDs -- Neuroinflammation -- Calcium Homeostasis, ER Stress, and Oxidative Stress in LSDs -- Description of Most Common Neurodegenerative LSDs Associated with Biometal Imbalance -- Gaucher Disease Type II and III -- Niemann Pick Type C1 -- Neuronal Ceroid Lipofuscinosis or Batten Disease -- Function and Regulation of Biometals -- Biometals in CNS -- Biometals in Lysosomes -- Loss of Biometal Homeostasis is Connected to Disease. , Role of Biometals and Biometal Binding Proteins in LSDs -- LSDs and Iron Homeostasis -- LSDs and Copper Homeostasis -- LSDs and Zinc Homeostasis -- Targeting Metals to Treat Disease -- References -- Chapter 12 - Developmental Exposure to Metals and its Contribution to Age-Related Neurodegeneration -- Introduction -- Developmental Exposure to Toxicants and Late Effects -- Developmental Lead Exposure and Alzheimer's Disease -- Developmental Arsenic Exposure and Alzheimer's Disease -- Conclusions and Future Perspectives -- Acknowledgment -- References -- Chapter 13 - Metal Biology Associated with Huntington's Disease -- Introduction -- The Epidemiology of HD -- The Symptoms of HD -- The Neuropathology of HD -- Biological Function of Wild-type and Pathogenic HTT Proteins -- Autophagy and Metals in Huntington's Disease -- Exosomes and Metal in Huntington's Disease -- Environmental Factors Impacting HD -- Metals in HD -- Iron in HD -- Copper in HD -- Calcium in HD -- Manganese in HD -- Manganese Deposition: Brain Regions, Cell Types, and Cellular Organelles -- Regional Deposition -- Cell-Type Deposition -- Subcellular Deposition -- Manganese Dyshomeostasis in HD -- Mn-Dependent and Mn-Utilizing Enzymes -- GS-Glutamine Synthetase -- SOD2-Mn-Dependent Superoxide Dismutase -- ARG1 and ARG2-Arginase -- ATM-Ataxia Telangiectasia Mutated -- MRE-11-Meiotic Recombination 11, and FAN1-Fanconi's Associated Nuclease 1 -- Intracellular pH and Metal Biology in HD -- Metal-Related Clinical Interventions in HD -- Conclusions and Future Directions -- References -- Chapter 14 - Metal-Binding to Amyloid-β Peptide: Coordination, Aggregation, and Reactive Oxygen Species Production -- Introduction -- Interest in Chemistry of Metal-Amyloid-β Complexes -- Structure of the Metal-Aβ Complexes -- Coordination of Metal Ions Cu, Zn, and Fe to Soluble, Monomeric Amyloid-β. , Cu(II)-β-Amyloid -- Cu(I)-β-Amyloid -- Zn(II)-β-Amyloid -- Fe(II)-β-Amyloid -- Cu(II) Coordination to Aβ With Disease Relevant Mutations or Other Derivatives -- Coordination of Metal Ions Cu and Zn to Aggregated β-Amyloid -- Cu(II) Coordination to Aggregated Aβ Peptide -- Cu(I) Coordination to Aggregated Aβ Peptide -- Zn(II) Coordination to Aggregated Aβ Peptide -- Affinity of Metals to Aβ -- Affinity of Metal Ions Cu(I/II) and Zn(II) to Soluble, Monomeric Amyloid-β -- Affinity of Metal Ions Cu(I/II) and Zn(II) to Aggregated β-Amyloid -- Cu(II) versus Zn(II) Binding -- Aggregation -- General Consideration for Aβ -- Impact of Metal Ions on Aβ Aggregation -- Reactive Oxygen Species Induced Oxidative Stress -- Reactive Oxygen Species Production by Cu-Aβ Complexes -- Cu-Aβ and ROS Production -- Redox Chemistry of Cu-Aβ Complexes by Cyclic Voltammetry -- Mechanism of ROS Production and the Reactive State of Cu-Aβ Complexes -- The Fenton type reaction -- Dioxygen Reduction -- Efficiency and Biological Relevance of the ROS Production by Cu-Aβ Complexes -- Conclusions -- Acknowledgments -- References -- Chapter 15 - Metals and Mitochondria in Neurodegeneration -- Introduction -- Iron Dyshomeostasis -- Copper Dislocation -- Zinc Deficiency -- Mitochondrial Dysfunction -- Conclusions -- Acknowledgments -- References -- Chapter 16 - Metal Transporters in Neurodegeneration -- Iron Transporters and Neurodegeneration -- Tf-TfR -- DMT1 -- Fpn -- Lf-LfR -- MTf -- Iron Transporters and PD -- Iron Transporters and AD -- Iron and Other Neurodegenerative Disorders -- Zinc Transporters and Neurodegeneration -- ZnT -- ZIP -- MTs -- Zinc Transporters and PD -- Zinc Transporters and AD -- Zinc Transporters and Other Neurodegenerative Diseases -- Copper Transporters and Neurodegeneration -- CTR1 -- The ATPases ATP7A/ATP7B -- Copper Transporters and PD. , Copper Transporters and AD.
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  • 2
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The major component of the amyloid deposition that characterizes Alzheimer's disease is the 4-kDa βA4 protein, which is derived from a much larger amyloid protein precursor (APP). A procedure for the complete purification of APP from human brain is described. The same amino terminal sequence of APP was found in two patients with Alzheimer's disease and one control subject. Two major forms of APP were identified in human brain with apparent molecular masses of 100–110 kDa and 120–130 kDa. Soluble and membrane fractions of brain contained nearly equal amounts of APP in both humans and rats. Immunoprecipitation with carboxyl terminus-directed antibodies indicates that the soluble forms of APP are truncated. Carboxyl terminus truncation of membrane-associated forms of human brain APP was also found to occur during postmortem autolysis. The availability of purified human brain APP will facilitate the investigation of its normal function and the events that lead to its abnormal cleavage in patients with Alzheimer's disease.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Oxidative stress may have an important role in the progression of neurodegenerative disorders such as Alzheimer's disease (AD) and prion diseases. Oxidative damage could result from interactions between highly reactive transition metals such as copper (Cu) and endogenous reducing and/or oxidizing molecules in the brain. One such molecule, homocysteine, a thiol-containing amino acid, has previously been shown to modulate Cu toxicity in HeLa and endothelial cells in vitro. Due to a possible link between hyperhomocysteinemia and AD, we examined whether interaction between homocysteine and Cu could potentiate Cu neurotoxicity. Primary mouse neuronal cultures were treated with homocysteine and either Cu (II), Fe (II or III) or Zn (II). Homocysteine was shown to selectively potentiate toxicity from low micromolar concentrations of Cu. The toxicity of homocysteine/Cu coincubation was dependent on the ability of homocysteine to reduce Cu (II) as reflected by the inhibition of toxicity with the Cu (I)-specific chelator, bathocuproine disulphonate. This was supported by data showing that homocysteine reduced Cu (II) more effectively than cysteine or methionine but did not reduce Fe (III) to Fe (II). Homocysteine also generated high levels of hydrogen peroxide in the presence of Cu (II) and promoted Aβ/Cu-mediated hydrogen peroxide production and neurotoxicity. The potentiation of metal toxicity did not involve excitotoxicity as ionotropic glutamate receptor antagonists had no effect on neurotoxicity. Homocysteine alone also had no effect on neuronal glutathione levels. These studies suggest that increased copper and/or homocysteine levels in the elderly could promote significant oxidant damage to neurons and may represent additional risk factor pathways which conspire to produce AD or related neurodegenerative conditions.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cu and Zn have been shown to accumulate in the brains of Alzheimer's disease patients. We have previously reported that Cu2+ and Zn2+ bind amyloid β (Aβ), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu2+-binding sites on synthetic Aβ1-40 and Aβ1-42. We have developed a ligand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to Aβ, a notoriously self-aggregating peptide. This analysis indicated that there is a very-high-affinity Cu2+-binding site on Aβ1-42 (log Kapp = 17.2) that mediates peptide precipitation and that the tendency of this peptide to self-aggregate in aqueous solutions is due to the presence of trace Cu2+ contamination (customarily ∼0.1 μM). In contrast, Aβ1-40 has much lower affinity for Cu2+ at this site (estimated log Kapp = 10.3), explaining why this peptide is less self-aggregating. The greater Cu2+-binding affinity of Aβ1-42 compared with Aβ1-40 is associated with significantly diminished negative cooperativity. The role of trace metal contamination in inducing Aβ precipitation was confirmed by the demonstration that Aβ peptide (10 μM) remained soluble for 5 days only in the presence of high-affinity Cu2+-selective chelators.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 72 (1999), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-1-nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-β (Aβ) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Aβ25-35 in the presence or absence of Cu or Fe. Aβ25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Aβ to perturb neuronal GSH homeostasis. Aβ25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: To study amyloid β-protein (Aβ) production and aggregation in vivo, we created two transgenic (Tg) mouse lines expressing the C-terminal 100 amino acids of human amyloid precursor protein (APP): Tg C100.V717F and Tg C100.WT. Western blot analysis showed that human APP-C100 and Aβ were produced in brain and some peripheral tissues and Aβ was produced in serum. Using antibodies specific for the Aβ C terminus we found that Tg C100.V717F produced a 1.6-fold increase in Aβ42/Aβ40 compared with Tg C100.WT. Approximately 30% of total brain Aβ (∼122 ng/g of wet tissue) was water-soluble. The remaining 70% of Aβ partitioned into the particulate fraction and was completely sodium dodecyl sulfate-soluble. In contrast, human Alzheimer's disease brain has predominantly sodium dodecyl sulfate-insoluble Aβ. Immunohistochemistry with an Aβ(5-8) antibody showed that Aβ or Aβ-containing fragments accumulated intracellularly in the hippocampus of aged Tg C100.V717F mice. The soluble Aβ levels in Tg brain are similar to those in normal human brain, and this may explain the lack of microscopic amyloid deposits in the Tg mice. However, this mouse model provides a system to study the intracellular processing and accumulation of Aβ or Aβ-containing fragments and to screen for compounds directed at the γ-secretase activity.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 695 (1993), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Notes: βA4, the principal constituent of the brain amyloid collections in Alzheimer's disease, is derived from a much larger precursor, the amyloid protein precursor (APP). APP exists in the blood as full-length, potentially amyloidogenic forms in platelets, and as an attenuated species in plasma and T-lymphocytes. Studies of circulating APP facilitate the elaboration of the function of this protein, as well as the elucidation of its processing in health and disease.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-4943
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    Publication Date: 2022-01-07
    Description: Highlights • Regional brain iron concentrations are heterogenous. • Regional distribution of iron is most consistent with ferritin mRNA expression. • SEC-ICP-MS reveals the protein masses that cytosolic iron is associated with. • More than 50 % of cytosolic iron is associated with ferritin. Iron is essential for brain development and health where its redox properties are used for a number of neurological processes. However, iron is also a major driver of oxidative stress if not properly controlled. Brain iron distribution is highly compartmentalised and regulated by a number of proteins and small biomolecules. Here, we examine heterogeneity in regional iron levels in 10 anatomical structures from seven post-mortem human brains with no apparent neuropathology. Putamen contained the highest levels, and most case-to-case variability, of iron compared with the other regions examined. Partitioning of iron between cytosolic and membrane-bound iron was generally consistent in each region, with a slightly higher proportion (55 %) in the ‘insoluble’ phase. We expand on this using the Allen Human Brain Atlas to examine patterns between iron levels and transcriptomic expression of iron regulatory proteins and using quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry to assess regional differences in the molecular masses to which cytosolic iron predominantly binds. Approximately 60 % was associated with ferritin, equating to approximately 25 % of total tissue iron essentially in storage. This study is the first of its kind in human brain tissue, providing a valuable resource and new insight for iron biologists and neuroscientists, alike.
    Type: Article , PeerReviewed
    Format: text
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